Appl Microbiol Biotechnol DOI 10.1007/s00253-015-6553-x

MINI-REVIEW

Antibacterial products of marine organisms Tzi Bun Ng 1 & Randy Chi Fai Cheung 1 & Jack Ho Wong 1 & Adnan A. Bekhit 2 & Alaa El-Din Bekhit 3

Received: 20 November 2014 / Revised: 17 March 2015 / Accepted: 19 March 2015 # Springer-Verlag Berlin Heidelberg 2015

Abstract Marine organisms comprising microbes, plants, invertebrates, and vertebrates elaborate an impressive array of structurally diverse antimicrobial products ranging from small cyclic compounds to macromolecules such as proteins. Some of these biomolecules originate directly from marine animals while others arise from microbes associated with the animals. It is noteworthy that some of the biomolecules referred to above are structurally unique while others belong to known classes of compounds, peptides, and proteins. Some of the antibacterial agents are more active against Gram-positive bacteria while others have higher effectiveness on Gramnegative bacteria. Some are efficacious against both Grampositive and Gram-negative bacteria and against drugresistant strains as well. The mechanism of antibacterial action of a large number of the chemically identified antibacterial agents, possible synergism with currently used antibiotics, and the issue of possible toxicity on mammalian cells and tissues await elucidation. The structural characteristics pivotal to antibacterial activity have been ascertained in only a few studies. Demonstration of efficacy of the antibacterial agents

* Tzi Bun Ng [email protected] * Randy Chi Fai Cheung [email protected] * Jack Ho Wong [email protected] 1

School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China

2

Faculty of Pharmacy, Alexandria University, Alexandria 21521, Egypt

3

Department of Food Science, University of Otago, Dunedin, New Zealand

in animal models of bacterial infection is highly desirable. Structural characterization of the active principles present in aqueous and organic extracts of marine organisms with reportedly antibacterial activity would be desirable. Keywords Antibacterial . Marine organisms . Products

Introduction Natural products have long served as sources of antibacterial agents. The discovery of the antibiotic activity of Penicillium notatum in 1929 by Fleming has revolutionized medical science, leading to the invention of the wonder drug Bpenicillin.^ Other well-known examples included cephalosporin, vanomycin, and carbapenem. However, with the increasing usage of these drugs, bacterial strains that develop drug resistance to these antibiotics have been reported everywhere (Bassetti et al. 2013; Rice 2006). Thus, the development of new drugs or alternative therapies is clearly a matter of urgency. The number of antibiotics that have been isolated from terrestrial organisms is far exceeds the number that have been obtained from marine sources (Kanagasabapathy et al. 2011). Natural products derived from marine organisms are structurally diverse and also differ from those identified from terrestrial organisms. They can be used to design and develop new, potentially useful therapeutic agents. It is clear that many marine organisms have not yet been extensively studied and can serve as a vast source of potential ready-made pharmaceutical agents (Aneiros and Garateix 2004). The oceans occupy a large proportion of the Earth’s surface and the bulk of the biosphere. Marine organisms produce a constellation of biomolecules for survival in an environment in which they face intense competition with pathogenic microbes (Ammerman et al. 1984).

Appl Microbiol Biotechnol

This review comprises a description of some of the recent works (2005–2014), with emphasis on research aimed at the development of antibacterial products from marine organisms. The products were sorted according to the classification of the species that produce them. Bioactive compounds from terrestrial organisms have a long history of medicinal applications when compared with the notorious marine compounds, such as shellfish paralytic toxins, fish neurotoxins, and cyanotoxin from cyanobacteria. Until recent years, we have witnessed growing attention to an alternative view of marine natural products (Chin et al. 2006). They provide a rich source of chemical diversity that can be used to design and develop new, potentially useful therapeutic agents (Barboza et al. 2012; Martin et al. 2013; Tsoukalas et al. 2014). The vast majority of currently used antibiotics have been isolated from terrestrial sources, and recent research strongly suggests that the marine environment represents an untapped source of new bioactive molecules (Kang et al. 2015; Valliappan et al. 2014). In this respect, marine bacteria and fungi seem to be the most prominent sources for antibacterial agent discovery due to their diversity and ability to grow rapidly and sustainably in bioreactors. Other sources, like algae, sponges, corals, mollusks, and other marine animals, can also supply interesting scaffolds or leads for drug discovery, which can be reproduced through chemical synthesis. Most antibiotics of bacterial origin originate from the Gram-positive soil bacteria of the order Actinomycetes such as Streptomyces sp. However, it is now clear that the rate of discovery of novel antibiotics from the soil bacteria is decreasing even though many studies have been done to discover new antibiotics or candidate compounds (Nathan 2004; von Nussbaum et al. 2006). In these respects, there are enormous works on developing antimicrobials or antibiotics from various natural resources, which can be potential candidates during the last few decades. Much effort was made in the investigations on marine actinomycetes for searching potential antimicrobial or antibiotics (Dasari et al. 2012; Haste et al. 2012; Jiao et al. 2013; Wang et al. 2013b; Zhou et al. 2012a). The Infectious Disease Society of America expressed concern in a policy report on April 2013 over the availability of antibiotics to combat antibiotic-resistant bacteria, especially Gramnegative bacilli (GNB), in view of the approval in the USA of only a couple of new antibiotics since 2009, and the number of new antibiotics approved each year continues to dwindle. The report could identify only seven antibiotics currently in phase 2 or phase 3 clinical trials to treat the GNB, and these drugs do not address the entire spectrum of the resistance developed by those bacteria (Boucher et al. 2013). One attractive approach against preventing antibiotic resistances is finding new compounds that are not based on the existing antibacterial agents. Marine microorganisms living in environments with extreme variations in pressure, salinity, and

temperature have developed unique metabolic and physical capabilities for survival in extreme habitats (Fenical 1993). They may produce potential metabolites that would not be discovered from terrestrial organisms (Donia and Hamann 2003). The information presented in this review suggested that marine bacteria would be a good source of antibacterial products. Selected marine products with antibacterial activities described in this article are summarized in Table 1. It is noteworthy that some antibacterial compounds exhibited minimum inhibitory concentrations (MICs) against methicillin resistant Staphylococcus aureus (MRSA) comparable or lower than that of vanomycin (2 μg/ml).

History and opportunities in development of marine antibacterial agents Natural products have a long history of being used as raw materials for medicine, and it is still true and they are regarded as the most important source of potential drug leads source nowadays with more than one million new chemical entities discovered until now (Carter 2011). At present, approximately 60 % of the drugs on the market are derivatives based on or made directly from natural products (Newman and Cragg 2012). These compounds are considered as better lead structures for medicine than the unnatural ones due to their higher chemical diversity, biochemical specificity, binding efficiency, and better propensity to interact with biological targets (Martins et al. 2014). In the 1950s, the discovery of the nucleosides spongothymidine and spongouridine in the Cryptotethya crypta (marine sponge) first drew the attention of the pharmaceutical industry to marine bioactive molecules (Bergmann and Feeney 1950, 1951). These nucleosides were later derivatized to form ara-C and ara-A. The former is an anticancer drug which is considered as the first marine species-related drug approved for clinical use in 1969; the latter is an antiviral against HSV. Another study on antibacterial activities from marine species disclosed that the crude extract of some marine sponges exhibited such activities against Gram-positive and Gram-negative bacteria (Burkholder and Ruetzler 1969). Since then, many new bioactive molecules with antibacterial properties have been isolated from marine sources each year (Blunt et al. 2015). Though an enormous number of marine-derived antibacterial agents have been discovered, all of them are still under investigation. Some of them have the potential for commercial development into medications and have arrived at the preclinical assessment stage, but so far, none of them has made to the drug market. There is a general trend that investigators of natural products and pharmaceutical companies were more interested in anticancer drugs nowadays. They invest more resources and efforts in the discovery and development of anticancer drugs and less on antibiotics. At present, several

Pseudoalteromonas phenolica O-BC30(T) (Isnansetyo and Kamei 2009) Alcaligens faecalis AU01 (Annamalai et al. 2011)

Bacteria

Dicarboxylic acid Protein Lipopeptide

MC21-B/1–4 μg/ml Alkaline protease Peptidolipins B and E/64 μg/ml

Bacteriocin

Lactococcus lactis strain PSY2 (Sarika et al. 2012)

Bacillus subtilis and Escherichia coli

Bipyridine alkaloid

Caerulomycin A and C/9.7–38.6 μM Fradimycins A, B, and MK844mF10/2.0–6.0 μg/ml 4-Dehydro-4a-dechlorona pyradiomycin A1, 3-dechloro3-bromonapyradiomycin A1, 3-chloro-6, 8-dihydroxy8-α-lapachone, napyradiomycin A1, 18-oxonapyradiomycin A1, napyradiomycin B1,

Actinoalloteichus cyanogriseus WH1-2216-6 (Fu et al. 2011b)

Streptomyces fradiae strain PTZ0025 (Xin et al. 2012) Streptomyces species strain SCSIO 10428 (Wu et al. 2013)

Escherichia coli, Aerobacter aerogenes, and Pseudomonas aeruginosa

MRSA, Acinetobacter baumannii, Pseudomonas aeruginosa, Escherichia coli, Staphylococcus aureus, and Bacillus subtilis

Staphylococcus aureus, Bacillus subtilis, and Bacillus thuringensis

Sulfoxide alkaloid

Xinghaiamine A/0.174–11.04 μM/ml

Streptomyces xinghaiensis NRRL B24674(T) (Jiao et al. 2013)

Bacillus subtilis, Bacillus pumilus, Staphylococcus aureus, Aeromonas formicans, Escherichia coli

naphthoquinone

Pyridinium salt

1(10-aminodecyl) pyridinium/ 70–160 μg/ml

MRSA and MSSA

MRSA and VRE

Staphylococcus aureus

Chlorinated bisindolepyrroles Thiopeptide

Lynamicins A-E/2.2–6.2 μg/ml

MRSA and vancomycin-resistant Enterococcus faecium

Bacillus subtilis

Staphylococcus aureus, Enterococcus faecalis, and Bacillus thuringensis

Anthraquinones

4-Oxazolidinone

Lipoxazolidinone A/1–2 μg/ml

Nosiheptide/0.03–0.25 mg/ml

α-Pyrone

Nocapyrones E-G/12–26 μM

Nocardiopsis dassonvillei HR10-5 (Fu et al. 2011a) Actinomycete strain NPS8920 (Sunga et al. 2008)

Actinomycete strain NPS12745 (McArthur et al. 2008) Actinomycete strain CNT-373 (Haste et al. 2012) Actinomycete strain DVR D4 (Dasari et al. 2012)

Diazaanthraquinone

Pseudonocardians A-C/1–4 μg/ml

Pseudonocardia strain SCSIO 01299 (Li et al. 2011)

Mycobacterium vaccae

Macrolactones Sesquiterpene

Macrolactins X-Z/8–32 μg/ml

Bacillus sp. (Mondol et al. 2013)

Streptomyces sp. HKI0595 (Ding et al. 2012) Kandenols A-E/12.5–25 μg/ml

Acinetobacter sp., Arthrobacter sp., Bacillus subtilis, Escherichia coli, Listeria monocytogenes, Pseudomonas aeruginosa, and Staphylococcus aureus

Staphylococcus aureus and Laribacter hongkongensis

Staphylococcus aureus

MRSA and VRE

Protein

Macrolides

MRSA and methicillin-sensitive Staphylococcus aureus (MSSA)

Flavobacterium sp., Pseudomonas fluorescens, Vibrio harveyi, Proteus sp., and Vibrio parahaemolyticus

MRSA, Bacillus subtilis, and Enterococcus serolicida

Susceptible bacterial spp.

Thiazolyl cyclic-peptide

Kocuria (MTCC 5269) (Mahajan et al. 2013) PM181104/0.004–2.048 μg/ml

Antimycin B2/8–32 μg/ml

Streptomyces lusitanus (Han et al. 2012)

Lipopeptide

Chemical class

Antibacterial products/MIC/testing system

Bacillus mojavensis B0621A (Ma et al. 2012) Mojavensin A and fengycin B

Nocardia sp. (Wyche et al. 2012)

Source organisms/reference

Antibacterial activities of selected marine products

Classification

Table 1

Appl Microbiol Biotechnol

Fungi

Classification

Staphylococcus aureus

γ-Butenolide Azaphilone

Spiculisporic acid B–D

Aspergillus sp. HDf2 (Wang et al. 2012)

Comazaphilones C/16–64 μg/ml

Penicitrinol J and K

Penicillium sp. ML226 (Wang et al. 2013a)

Staphylococcus aureus, Bacillus cereus, Vibrio parahemolyticus, and Staphylococcus albus Staphylococcus aureus

Benzofuran

Penicifuran A A/3.13–25 μM

Staphylococcus aureus and Pseudomonas aeruginosa

Bacillus cereus, Bacillus subtilis and Staphylococcus aureus

Xanthomonas campestris

Citrinin

Furan

5-Hydroxymethyl-furoic acid

Anthraquinone

Isorhodoptilometrin-1-methyl ether and siderin

Penicillium sp. strain FS60 (Zhang et al. 2012a) Penicillium sp. MWZ14-4 (Qi et al. 2013)

Dipeptide

Fellutanine

Penicillium sp. strain KF620 (Schulz et al. 2011) Aspergillus versicolor (Hawas et al. 2012)

Mycobacterium smegmatis, Mycobacterium bovis BCG, and Mycobacterium tuberculosis H37Rv

Staphylococcus epidermidis and Xanthomonas campestris Lipopeptide

Enterobacter aerogenes and Pseudomonas aeruginosa

Polyesters

Escherichia coli and Staphyloccocus aureus

Indole alkaloids Steroid

Trichoderins A, A1, and B/0.02–2.0 μg/ml

MRSA

Anthraquinones

Trichoderma sp. (Pruksakorn et al. 2010)

Staphylococcus albus, Bacillus subtilis, Bacillus cereus, Sarcina lutea, Escherichia coli, Micrococcus tetragenus, Vibro parahaemolyticus, and Vibrio anguillarum

Escherichia coli and Staphyloccocus aureus

MRSA and multidrug-resistant Staphylococcus aureus

Staphylococcus aureus, Pseudomonas aeruginosa, Enterobacter aerogenes, and Escherichia coli

Streptococcus faecalis, Escherichia coli, Pseudomonas aeruginosa, Vibrio fluvialis, Vibrio vulnificus, and Vibrio sp. N2

Mycobacterium tuberculosis and Bacillus cereus

Mycobacterium tuberculosis and Bacillus subtilis

Staphylococcus aureus and methicillin-resistant Staphylococcus epidermidis

Micrococcus luteus, Staphylococcus aureus, Bacillus subtilis, and Bacillus thuringiensis

Susceptible bacterial spp.

Sesquiterpenoid

Hydroquinone and benzyl alcohol Anthraquinones

Aspergillus flocculosus PT05-1 (Zheng et al. Ergosteroid 1,7-nor-ergosterolide and 2013) 3β-Hydroxyergosta-8, 24(28)-dien-7-one/1.6–15 μM Calcarisporium sp. KF525 (Silber et al. 2013) Calcarides A-C/5.5–68.8 μM

Toluhydroquinone and gentisyl alcohol/6.2–12.5 μg/ml Aspergillus versicolor (Miao et al. 2012) 6,8-Di-O-methylaverufin and 6-O-methylaverufin Aspergillus sp (Li et al. 2012) Aspergiterpenoid A, (−)-sydonol, (−)-sydonic acid, (−)-5-(hydroxymethyl)2-(2′,6′,6′-trimethyltetrahydro-2H-pyran2-yl) phenol/1.25–20.0 μM Trichoderma aureoviride PSU-F95 Coniothranthraquinone 1 and emodin/ (Khamthong et al. 2012) 4–8 μg/ml Eurotium cristatum EN-220 (Du et al. 2012) Cristatumins A/64 μg/ml

Pyranones

Nocardiopyrones A and B/20–48 μM

Nocardiopsis alkaliphila sp. nov. YIM-80379 (Wang et al. 2013b)

Dothideomycete sp. (Leutou et al. 2012)

Peptide

ε-Poly-l-lysine

Bacillus subtilis (El-Sersy et al. 2012)

Polyketide Cyclic depsipeptide

Lobophorin 2–5/1.3–24.4 μM Pitiprolamide

Streptomyces sp (Lin et al. 2014)

Sesquiterpenoid naphthoquinone

Cyclic peptide

napyradiomycin B3 and napyradiomycin SR/0.25–128 μg/ml Marthiapeptide A/2.0–8.0 μg/ml Marfuraquinocins A, C, and D/8.0 μg/ml

Chemical class

Antibacterial products/MIC/testing system

Lyngbya majuscule (Montaser et al. 2011)

Streptomyces niveus (Song et al. 2013)

Marinactinospora thermotolerans SCSIO 00652 (Zhou et al. 2012a)

Source organisms/reference

Table 1 (continued)

Appl Microbiol Biotechnol

Bromotyrosine

Halistanol trisulfate/512 g/ml

Petromica citrine (Marinho et al. 2012)

(5Z)-Dec-5-en-1-yl sulfate and (3E)-dec-3-en-1-yl sulfate Hepatopancreatic phospholipase A2/5–15 μg/ml

Mytilin-derived peptide-1 and peptide-2

Hexaplex trunculus (Zarai et al. 2012)

Mytilus coruscus (Yang et al. 2011)

Mollusks

Antilipopolysaccharide factor7/0.51–16.30 μM

Portunus trituberculatus (Liu et al. 2013)

Apostichopus japonicus (La et al. 2012)

Protein

Scygonadin/6.25–50 μM

Scylla paramamosain (Peng et al. 2012)

Polypeptide

Protein

Alkene sulfate

Protein

Protein

Manzamine alkaloid

Zamamiphidin A/32 μg/ml Antilipopolysaccharide factor-1 and 2/1.6–12.5 μM

Amphimedon sp (Kubota et al. 2013)

Scylla paramamosain (Liu et al. 2012)

Callyspongia aerizusa (Ibrahim et al. 2010)

Terpenoid Cyclic peptide

Clathric acid/32–64 g/ml Callyaerins A-F

Clathria compressa (Gupta et al. 2012)

Steroid sulfate oxoanion

Diterpene alkaloid

Ageloxime B/10–20 μg/ml Ianthelliformisamine A/35 μM

Suberea ianthelliformis (Xu et al. 2012)

Cyclopolypeptide

Escherichia coli and Sarcina lutea

Micrococcus luteus, Streptococcus pneumonia, Corynebacterium diphteriae, Enterococcus faecalis, Enterobacter cloacae, Bacillus subtilis, Bacillus cereus, Staphylococcus aureus, and Staphylococcus epidermidis

Escherichia coli

Vibrio alginolyticus, Edwardsiella tarda, Pseudomonas aeruginosa, and Staphyloccocus aureus

Aeromonas hydrophila, Pseudomonas fluorescens, Shigella flexneri, Escherichia coli, Vibrio harveyi, Micrococcus leteus, Staphylococcus aureus, Corynebacterium, Bacillus subtilis, Bacillus cereus, Staphylococcus epidermidis

Corynebacterium glutamicum, Bacillus subtilis, Micrococcus lysodeikticus, Micrococcus luteus, Escherichia coli, Shigella flexneri, Vibrio harveyi, Vibrio alginolyticus, Vibrio parahaemolyticus, Pseudomonas aeruginosa, Pseudomonas stutzeri, Pseudomonas fluorescens

Staphylococcus aureus

Staphylococcus aureus, Bacillus subtilis, and Escherichia coli,

Staphylococcus aureus, MRSA, and VRSA

Staphylococcus aureus, Staphylococcus epidermidis, Enterococcus faecalis, Mycobacterium fortuitum, and Neisseria gonorrhoeae.

Pseudomonas aeruginosa

MRSA and Staphylococcus aureus

Pseudomonas aeruginosa, Klebsiella pneumonia, Candida albicans, Trichophyton mentagrophytes, and Microsporum audouinii

Staphylococcus albus, Staphylococcus aureus, Escherichia coli, Pseudomonas putida, Nocardia brasiliensis, and Vibrio parahaemolyticus

Bacillus subtilis and Micrococcus luteus

Sesquiterpenoid

Steroid

Escherichia coli, Pseudomonas aerugenosa, Klebsiella pneumoniae, and Shigella flexineri

MRSA, Pseudomonas fluorescens, and Bacillus subtilis

Susceptible bacterial spp.

Sterol

Chemical class

Agelas mauritiana (Yang et al. 2012)

Stylissa caribica (Dahiya and Gautam 2010) Stylisin 2

(−)-4β-N-methenetauryl10β-methoxy-1β,5β,6α, 7α-aromadendrane 15β-Hydroxypregna-1,4,20-trien3-one/31 nM–4 μM

24-Propylidene cholest5-en-3β-ol/0.53–1.70 μg/ml

Antibacterial products/MIC/testing system

Echinoderms

Arthropods

Sponges

Melitodes squamata Nutting (Huang et al. 2012)

Cnidarians

Carijoa sp. (Zhao et al. 2013)

Laurencia papillosa (Kavita et al. 2013)

Penicillium commune QSD-17 (Gao et al. 2011)

Source organisms/reference

Algae

Classification

Table 1 (continued)

Appl Microbiol Biotechnol

Reptiles

Fish

Classification

Myticusin-1/1.25–25 μM

Ferritin H-like subunit

Ruditapes philippinarum (Kim et al. 2012)

Protein Protein

C-reactive protein Glyrichin Interferon regulatory factor 1 hepcidin/1.5–3 μM

Cynoglossus semilaevis (Li et al. 2013)

Oplegnathus fasciatus (Kasthuri et al. 2013)

Cynoglossus semilaevis (Lu et al. 2014)

Epinephelus coioides (Qu et al. 2013)

Truncated pleurocidin/ 1.9–3.8 μg/ml

Pleuronectes americanus (Choi and Lee 2012)

Protein

Protein Protein

Truncated Epinecidin-1

Epinephelus coioides (Huang et al. 2013)

Defensin-like egg white protein

Protein

A chicken-type lyzoyme

Scophthalmus maximus (Yu et al. 2013)

Caretta caretta (Chattopadhyay et al. 2006)

Protein

Scophthalmus maximus (Zhang et al. 2014a) Hepcidin-1 and 2/1–8 μM

Protein

Protein

Protein

l-Amino acid oxidase/0.078–0.63 μg/ml

Sebastes schlegelii (Kitani et al. 2013)

Escherichia coli and Salmonella typhimurium

Staphylococcus aureus, Enterococcus faecium, Propionibacterium acnes, Escherichia coli, and Pseudomonas aeruginosa

MRSA

Micrococcus luteus and Staphylococcus aureus

Edwardsiella tarda, Vibrio anguillarum, Micrococcus luteus, and Staphylococcus aureus

Pseudomonas stutzeri and Staphylococcus aureus

Vibrio anguillarum

Escherichia coli, Edwardsiella tarda, and Streptococcus iniae

Edwardsiella tarda, Vibrio anguillarum, Escherichia coli, Micrococcus luteus, and Streptococcus iniae

Aeromonas salmonicida, Aeromonas hydrophila, Photobacterium damselae, and Vibrio parahaemolyticus

Moritella viscose, Yersinia ruckeri, Vibrio anguillarum, Aeromonas sobria, Aeromonas hydrophila, Aeromonas salmonicida, Pseudomonas aeruginosa, Escherichia coli, Bacillus megaterium, and Lactobacillus sp.

Escherichia coli

Protein

Protein

Cathelicidin/5-80 μM

Gadus morhua (Broekman et al. 2011)

Escherichia coli

Vibrio tapetis

Escherichia coli, Vibrio Parahaemolyticus, Pseudomonas aeruginosa, Proteus vulgaris, Vibrio.harveyi, Bacillus subtilis, Staphylococcus aureus, Sarcina luteus, and Bacillus megaterium

Escherichia coli

Staphylococcus aureus and Escherichia coli

Susceptible bacterial spp.

Protein

Protein

Protein Protein

Tyrosinase

Mytilus coruscus (Liao et al. 2013)

Branchiostoma belcheri tsingtauense Vitellogenin (Zhang et al. 2005) Rachycentron canadum (Ngai and Ng 2007) Lectin/250 μg

Protein

Bactericidal protein

Cenchritis muricatus (LopezAbarrategui et al. 2012) Chlamys farreri (Zhou et al. 2012b)

Chemical class

Antibacterial products/MIC/testing system

Source organisms/reference

Table 1 (continued)

Appl Microbiol Biotechnol

Appl Microbiol Biotechnol

promising marine-derived drugs that reached the preclinical assessment and clinical trials were for anticancer, antiviral, and analgesic applications. Regarding the discovery of a bioactive natural product, say antibacterial product, usually a specific species is selected, the product is extracted, screened for antibacterial activity, subjected to purification procedures, and finally the product is isolated. Although the procedures are of a general and routine nature, this traditional way of natural product discovery is slow, tedious, labor-intensive, and low in efficiency. Today, the advancement made in sophisticated analytical and spectroscopic methods such as nuclear magnetic resonance and mass spectrometry has helped to enhance the efficiency of natural product discovery. It has allowed de novo structural determination of new chemical entities in very small concentrations even in crude extracts and complex partially purified fractions (Koehn and Carter 2005). Due to the continuous exploitation of the marine habitat, interest in searching for sources of natural products was diverted from sponges to microorganisms such as marine cyanobacteria, fungi, and bacteria because of their biological and habitat diversity. The structures of their natural products are rather unique and novel (Bhatnagar and Kim 2010). Microorganisms provide an abundant source of structurally diverse natural products and supply some of the most important active ingredients for medicine nowadays (Waters et al. 2010). It was also found that many compounds previously considered to have originated from marine macroorganisms, such as sponges and tunicates, are actually metabolic products from their associated microorganisms (Penesyan et al. 2010; Piel 2009). For the majority of the microorganisms which cannot be cultured, techniques such as metagenomics or genome mining can be used to spot the hidden natural product resources from these microorganisms. By employing DNA extraction of the entire environment, the metagenomic technique can explore the genome of the nonculturable microbial inhabitants. This technique was found to be a good substitute method for natural product discovery from noncultivable microorganisms (Culligan et al. 2014; Li and Qin 2005). By analyzing genome sequences of the noncultivable microorganisms, the genome mining technique can recognize the genes encoding the target proteins, which is also an alternative method for natural product discovery. It can also find out the gene clusters and new pathways for the biosynthesis of target natural compounds (Bachmann et al. 2014; Galm and Shen 2007). For the cultivable microorganisms, the problem of isolation of enough raw natural product materials is easily solved by adopting large-scale cultivation or fermentation. Since the marine environment is more diverse and higher in salt content than that in the terrestrial environment, we have used a different approach from terrestrial microorganisms to optimize the culture medium for the enhanced production of target biomolecules. Fortunately,

it is now easy to formulate the medium by small-scale, high-throughput cultivation methods that use nutrientdeficient media, specific nutrients, and long cultivation time (Kawanishi et al. 2011; Leeds et al. 2006). If the products arise from eukaryotic sources, large-scale cultivation is not feasible and the natural supply will not be adequate. The products have to be manufactured by complex chemical synthesis or semisynthesis from natural product intermediates (Wagner-Dobler et al. 2002). Bacteria Aqueous extracts and organic solvent extracts of nine of the marine cyanobacterial strains tested by Martins et al. (2008) exerted activity against two Gram-positive bacteria, Clavibacter michiganensis subsp. insidiosum and Cellulomonas uda, but there was no effect on Gramnegative bacteria. Marine Synechocystis and Synechococcus extracts also inhibited Gram-positive bacteria. The results indicate the presence of compounds with different polarities extractable by aqueous and organic solvents, respectively, although their structures remain obscure (Martins et al. 2008). MC21-B, the antibiotic 2,2′,3-tribromobiphenyl-4,4′-dicarboxylic acid produced by the marine bacterium Pseudoalteromonas phenolica O-BC30(T) exhibited antiMRSA activity against all ten clinical isolates of methicillinresistant Staphylococcus aureus (MRSA) examined, with MICs ranging from 1 to 4 μg/ml. MC21-B was also potent against Bacillus subtilis and Enterococcus serolicida but did not affect Gram-negative bacteria (Isnansetyo and Kamei 2009). Alcaligens faecalis AU01 isolated from seafood industry effluent produced a 33-kDa alkaline protease which was active between 30 and 70 °C with an optimum temperature at 55 °C and an optimum pH at 9. The protease was fairly stable: over 85 % activity was retained at 70 °C, and 78 % activity was recovered even at pH 10. The protease exerted a growthretarding action on piscine pathogens such as Flavobacterium sp., Pseudomonas fluorescens, Proteus sp., Vibrio harveyi, and V. parahaemolyticus (Annamalai et al. 2011). Thus, the protease may find application in fish culture. Four marine epibiotic bacterial spp. (Serratia marcescens V1, Bacillus sp. S3, B. pumilus S8, and B. licheniformis D1) with an inhibitory action toward B. pumilus .and Pseudomonas aeruginosa, upon coculture with the aforementioned bacteria, brought about induction or augmentation of antimicrobial activity, biosurfactant production, and quorumsensing inhibition. Antibacterial activity against P. aeruginosa PA or B. pumilus BP was enhanced in the majority of the marine isolates following coculture. A rise in biosurfactant activity was observed when B. pumilus cells were cocultured with S. marcescens V1, B. pumilus S8, or B. licheniformis D1. Pigment reduction in the quorum-sensing inhibition indicator

Appl Microbiol Biotechnol

strain Chromobacterium violaceum 12472 was observed when the inducer strain P. aeruginosa PA was cultured in the presence of Bacillus sp. S3, signifying quorum-sensing inhibition. The result of this investigation has ecological and biotechnological significance with reference to microbial competition in the natural environment and increased production of secondary metabolites (Dusane et al. 2011). A marine Nocardia species isolated from the ascidian Trididemnum orbiculatum produced five lipopeptides designated as peptidolipins B-F with resemblance to the L-Val analog of peptidolipin NA. Peptidolipins B and E demonstrated moderate antibacterial activity against MRSA and methicillinsensitive Staphylococcus aureus (Wyche et al. 2012). A triad of lipopeptides with a weak suppressive action on S. aureus, designated as mojavensin A, iso-C16 fengycin B, and anteiso-C17 fengycin B, respectively, were obtained from the fermentation broth of Bacillus mojavensis B0621A. The structure of mojavensin A had the unique characteristic of a peptide backbone of L-Asn (1), D-Tyr(2), D-Asn (3), LGln(4), L-Pro(5), D-Asn (6), L-Asn (7), and an anteiso-type of the saturated β-fatty acid side chain (Ma et al. 2012). From the marine sponges Leucosolenia sp. and Suberites carnosus, a large number (237) of bacterial species were isolated (Flemer et al. 2012). Most of the bacteria from S. carnosus were Pseudovibrio species, and antibacterial activity was detected in about half of the isolates. The major portion of the inhibitory activity against bacteria was attributed to isolates from Spongiobacter and Pseudovibrio species. Pseudoalteromonas and Vibrio species were the main bacteria isolated from Leucosolenia sponges. The data indicate that S. carnosus isolates contained compounds possessing antibacterial activity (Flemer et al. 2012). Different bacterial populations were found in the coastal sponges E. major and A. fucorum. Very few isolates produced metabolites with antibacterial activity in culture, but activity against Escherichia coli and Bacillus subtilis was common in Pseudovibrio spp. (Margassery et al. 2012). Antimycin B2, an antimycin A analog isolated from the spent broth of a marine-derived bacterium, Streptomyces lusitanus, exhibited antibacterial activity against L. hongkongensis with an MIC value of 8.0 μg/ml and against S. aureus with an MIC value of 32.0 μg/ml (Han et al. 2012). The Lactococcus lactis strain PSY2 isolated from the surface of the marine perch Perca flavescens produced bacteriocins with antibacterial activity against pathogenic and spoilage-causing Gram-positive and Gram-negative bacteria such as Staphylococcus aureus, Acinetobacter sp., Listeria monocytogenes, Arthrobacter sp., Escherichia coli, Pseudomonas aeruginosa, and Bacillus subtilis (Sarika et al. 2012). Most (83 %) of the Pseudoalteromonas strains collected from Red Sea corals demonstrated thermostable activity against Bacillus cereus and S. aureus (Shnit-Orland et al.

2012). Thermostability of drug candidates is a desirable feature for drug development. Anti-MRSA compounds are produced by Pseudoalteromonas piscicida PG-02, isolated from the Persian Gulf. A temperature of 28 °C, a pH of 7, NaCl at 0.5 % concentration, a duration of 96 h for incubation, and glucose as carbon source and tryptone as nitrogen source were optimal for maximum production. The antibacterial principle may be a protein as indicated by its heat lability and protease sensitivity. Transmission electron microscopy revealed disorganization of bacterial cytoplasmic membrane upon treatment with the extract (Darabpour et al. 2012). More detailed characterization of the active principle is warranted. A thiazolyl cyclic peptide antibiotic, PM181104 from a marine sponge associated actinobacterial strain of the genus Kocuria (MTCC 5269) displayed strong in vitro antibacterial activity against MRSA and vancomycin-resistant enterococci with nanomolar MIC values and an ED100 value of 2.5 and 5.0 mg/kg against MRSA and 10.0 mg/kg against VRE in vivo in a murine septicemia model (Mahajan et al. 2013). Macrolactins X-Z, which are 24-membered macrolactones with an oxetane, an epoxide, and a tetrahydropyran ring, respectively, obtained from the ethyl acetate extract of the fermentation broth of a marine Bacillus species, manifested antimicrobial activity in vitro (Mondol et al. 2013). Streptomyces sp. HKI0595 derived from the mangrove plant Kandelia candel produced eudesmene-type sesquiterpenes designated as kandenols A-E which demonstrated some antimicrobial activity against Mycobacterium vaccae and Bacillus subtilis (Ding et al. 2012). The diazaanthraquinone derivatives pseudonocardians AC, with MIC values of 1–4 μg/ml on Bacillus thuringensis, Enterococcus faecalis, and Staphylococcus aureus, were products of a marine actinomycete (strain SCSIO 01299) of the genus Pseudonocardia collected from deep-sea sediment of the South China Sea (Li et al. 2011). Nocapyrones E-G from the marine actinomycete Nocardiopsis dassonvillei HR10-5 exhibited activity against Bacillus subtilis with MIC values of 26, 14, and 12 μM, respectively (Fu et al. 2011a). A marine actinomycete strain NPS8920 produced lipoxazolidinone A, B, and C which belonged to a new class of 4-oxazolidinone antibiotics. Lipoxazolidinone A displayed good antimicrobial potency against drug-resistant pathogens MRSA and VRE. The optimal production of lipoxazolidinones was observed in the natural seawaterbased medium (Sunga et al. 2008). Lynamicins A-E, chlorinated bisindole pyrroles from a marine actinomycete NPS12745 with the genus name Marinispora, isolated from marine sediment collected from the coast of San Diego, CA, possessed broad-spectrum activity against both Gram-positive and Gram-negative organisms, and against MRSA and VRE (McArthur et al. 2008).

Appl Microbiol Biotechnol

The thiopeptide antibiotic nosiheptide from a marine actinomycete strain manifested high potency against all MRSA strains tested including multidrug-resistant clinical isolates, with MIC values at or below 0.25 μg/ml. The anti-MRSA activity of nosiheptide was preserved in the presence of 20 % human serum and lasted longer than that of vancomycin. Nosiheptide was also effective in MRSA-infected mice. Nosiheptide was also very active against Enterococcus spp. and the hypervirulent BI/NAP1/027 strain of Clostridium difficile but was devoid of activity against the majority of Gram-negative strains and toxicity against mammalian cells (Haste et al. 2012). The lack of toxic action of drug candidates on mammalian cells is a desirable feature for drug development. Marine sediment samples collected from Visakhapatnam coast of Bay of Bengal, India, were investigated as a source of marine actinomycetes. A cytotoxic compound, 1(10aminodecyl) pyridinium salt antibiotic, was produced by Amycolatopsis alba var. nov. DVR D4. Actinomycete strain DVR D4, exerted an antibacterial action against Grampositive and Gram-negative bacteria (Dasari et al. 2012). The angucyclines saccharothrixmicines A and B, and diketopiperazines 4–6 were isolated from Saccharothrix espanaensis An 113, an actinomycete associated with the marine mollusk Anadara broughtoni. Saccharothrixmicines A is an alpha- L-6 -deox yaltrose -phe nylglyc oside of a benz[α]anthraquinone aglycon while saccharothrixmicines B is an O-glycoside of the same sugar bound to C-7 of the known angucyclinone. A fraction with saccharothrixmicine as one of the components demonstrated inhibitory activity toward Xan tho mon as sp. pv. badrii wh ereas the diketopiperazines exerted a suppressive action on Vibrio alginolyticus and V. parahaemolyticus (Kalinovskaya et al. 2010). Xinghaiamine A, a highly symmetric alkaloid from the fermentation broth of a marine-derived actinomycete Streptomyces xinghaiensis NRRL B24674(T), expressed antibacterial activity toward both Gram-negative persistent hospital pathogens (including Acinetobacter baumannii, Escherichia coli, and Pseudomonas aeruginosa) and Grampositive pathogens such as Bacillus subtilis and Staphylococcus aureus (Jiao et al. 2013). Caerulomycin A and C were isolated from the marinederived actinomycete, Actinoalloteichus cyanogriseus WH12216-6. They manifested antimicrobial activity against Aerobacter aerogenes, Escherichia coli, and Pseudomonas aeruginosa with MIC values of 9.7 to 38.6 μM (Fu et al. 2011b). Capoamycin-type antibiotics were isolated from marine Streptomyces fradiae strain PTZ0025. Fradimycins A and B were found to be new, together with MK844-mF10 showed in vitro antimicrobial activity against Staphylococcus aureus with a minimal inhibitory concentration of 2.0 to 6.0 μg/ml (Xin et al. 2012).

Three new napyradiomycins, 4-dehydro-4a-dechlorona pyradiomycin A1, 3-dechloro-3-bromonapyradiomycin A1, and 3-chloro-6, 8-dihydroxy-8-α-lapachone, together with six known related analogues napyradiomycin A1, 18oxonapyradiomycin A1, napyradiomycin B1, napyradiomycin B3, and napyradiomycin SR were isolated from the culture broth of a marine-derived Streptomyces species actinomycete strain SCSIO 10428. Their antibacterial activity against three Gram-positive bacteria Staphylococcus and Bacillus strains have MIC values in the range 0.25– 32 μg/ml, with the exception that 3-chloro-6, 8-dihydroxy8-α-lapachone had a MIC value exceeding 128 μg/ml against Staphylococcus aureus ATCC 29213 (Wu et al. 2013). Marthiapeptide A, a new sequential tristhiazole-thiazolinecontaining cyclic peptide, was isolated from a 60-l culture of Marinactinospora thermotolerans SCSIO 00652 derived from deep South China Sea. Marthiapeptide A exhibited antibacterial activity against a panel of Gram-positive bacteria, with MIC values ranging from 2.0 to 8.0 μg/ml (Zhou et al. 2012a). The sesquiterpenoid naphthoquinones obtained from the deep South China Sea-derived Streptomyces niveus, marfuraquinocins A, C, and D, showed antibacterial activity against Staphylococcus aureus while marfuraquinocins C and D inhibited methicillin-resistant Staphylococcus epidermidis (Song et al. 2013). A new lumun-lumun sampling strategy was adopted to obtain a big variety of micromollusks, including the new species Lienardia totopotens. In turn, from L. totopotens a Streptomyces sp. strain that contained new and known spirotetronate polyketides, lobophorins, was cultured. Lobophorins 2–5 exhibited activity against M. tuberculosis and B. subtilis in the low micromolar to mid nanomolar range (Lin et al. 2014). A cyclic depsipeptide, pitiprolamide with proline representing half of the residues and a 4-phenylvaline (dolaphenvaline, Dpv) moiety was isolated from the marine cyanobacterium Lyngbya majuscula collected at Piti Bomb Holes, Guam. It showed weak antibacterial activities against Mycobacterium tuberculosis and Bacillus cereus (Montaser et al. 2011). ε-Poly-L-lysine active against a number of gram negative bacteria was first reported from Bacillus subtilis SDNS isolated from sea water in Alexandria active against a number of gram negative bacteria (El-Sersy et al. 2012). Two new pyran-2-ones, nocardiopyrones A and B, along with four known compounds, pyridinols, and 1-acetyl-βcarboline were isolated from the alkalophilic actinomycete Nocardiopsis alkaliphila sp. nov. YIM-80379. Their structures were established on the basis of spectroscopic analysis, CD spectra, and the quantum-chemical ECD calculation. Pyridinols were first isolated from a natural source. Nocardiopyrones A and B were weakly active against Enterobacter aerogenes, Escherichia coli, and Pseudomonas

Appl Microbiol Biotechnol

aeruginosa, with MIC values in the range of 20–48 μM. Nocardiopyrone B also expressed weak antimicrobial activity against Staphylococcus aureus with an MIC value of 48 μM (Wang et al. 2013b). Fungi When NaBr was present in the fermentation medium of a marine isolate of Dothideomycete sp., it triggered the generation of toluhydroquinone, two of its derivatives and gentisyl alcohol. These compounds displayed potent activity against MRSA and multidrug-resistant S. aureus with MIC values of 6.2, 6.2, 12.5, and 12.5 μg/ml, respectively (Leutou et al. 2012). Brevianamide M, 6,8-di-O-methylaverufin, and 6-Omethylaverufin with antibacterial activity against E. coli and S. aureus were obtained from the culture of Aspergillus versicolor, a fungus isolated from the marine brown alga Sargassum thunbergii (Miao et al. 2012). A quadruplet of bisabolane-type sesquiterpenoids, including (−)-sydonol, (−)-sydonic acid, aspergiterpenoid A, and (−)-5-(hydroxymethyl)-2-(2′,6′,6′-trimethyltetrahydro-2H-pyran-2-yl) phenol were isolated from the fermentation broth of a marine Aspergillus sp., isolated from Xestospongia testudinaria, a South China Sea sponge. The sesquiterpenoids displayed MIC values against eight bacterial strains ranging between 1.25 and 20.0 μM (Li et al. 2012). Trichodermaquinone and trichodermaxanthone as well as eleven known compounds were isolated from the marinederived fungus Trichoderma aureoviride PSU-F95. Coniothranthraquinone 1 and emodin displayed potent antiMSRA activity with the MIC values of 8 and 4 μg/ml, respectively (Khamthong et al. 2012). Aspergillus and Penicillium species were the most diverse and common fungal species associated with the six South China Sea gorgonian species studied by (Zhang et al. 2012b). The gorgonian Dichotella gemmacea and Echinogorgia aurantiaca had the highest and lowest fungal diversity, respectively. Nearly 40 % of the 121 fungal isolates examined demonstrated antibacterial and antifungal activities, signifying that the fungi may reinforce the defense of their gorgonian hosts against pathogenic microorganisms (Zhang et al. 2012b). Eurotium cristatum EN-220, an endophytic fungus isolated from the marine alga Sargassum thunbergi produce, when cultured, four indole alkaloids, namely, cristatumins A-D together with six known congeners. The compounds showed antibacterial activity against E. coli and S. aureus (Du et al. 2012). Ergosteroid 1, 3β-hydroxyergosta-8,24(28)-dien-7-one, and 7-nor-ergosterolide isolated from the fermentation broth of halotolerant A. flocculosus PT05-1 (obtained from the sediment of Putian saltern of Fujian Province in China) cultured

in a 10 % saline medium, showed activity against E. aerogenes and P. aeruginosa with MIC values in the range of 1.6–15 μM (Zheng et al. 2013). Five known polyesters, 15G256α, α-2, β, β-2 and π, and five new derivatives designated as calcarides A-E, with antibacterial activity against Propionibacterium acnes, Staphylococcus epidermidis, and Xanthomonas campestris, were purified from crude extracts of the fungus Calcarisporium sp. KF525 isolated from German Wadden Sea water samples (Silber et al. 2013). Three antimycobacterial aminolipopeptides, designated trichoderins A, A1, and B from a culture of marine spongederived fungus Trichoderma sp., showed potent antimycobacterial activity against Mycobacterium smegmatis, Mycobacterium bovis BCG, and Mycobacterium tuberculosis H37Rv under standard aerobic growth conditions as well as dormancy-inducing hypoxic conditions, with MIC values in the range of 0.02–2.0 μg/ml (Pruksakorn et al. 2010). Diketopiperazine fellutanine (cyclo(Trp-Trp)) in the Penicillium sp. strain KF620 isolated from the North Sea showed antimicrobial activities against Xanthomonas campestris (Schulz et al. 2011). The fungus Aspergillus versicolor isolated from the inner tissue of the Red Sea green alga Halimeda opuntia was identified by its morphology and 18S rDNA. The culture of this fungal strain produced a new metabolite isorhodoptilometrin1-methyl ether along with siderin. The ethyl acetate extract and the compounds were tested for antimicrobial activity (Hawas et al. 2012). 5-Hydroxymethyl-furoic acid isolated from the culture of Penicillium sp. strain FS60 from the South China Sea is demonstrated to have significant inhibition against S. aureus and P. aeruginosa (Zhang et al. 2012a). The fungal metabolite penicifuran A, obtained from the sponge-derived fungus Penicillium sp. MWZ14-4 collected from the South China Sea, exhibited anti-Staphylococcus albus activity with an MIC value of 3.13 μM (Qi et al. 2013). Four new citrinin derivatives, including two citrinin dimers and two citrinin monomer derivatives, were isolated and identified from a marine-derived fungal strain Penicillium sp. ML226 along with six known related compounds. The new compounds showed weak antimicrobial activity against Staphylococcus aureus (Wang et al. 2013a). Spiculisporic acids B–D are three new γ-butenolide derivatives from a sea urchin-derived fungus Aspergillus sp. HDf2. Their inhibitory activities against Staphylococcus aureus ATCC 51650 were investigated (Wang et al. 2012). Comazaphilones C–E, which are azaphilone derivatives from Penicillium commune QSD-17, a fungus isolated from a marine sediment sample collected in the Southern China Sea, were highly potent against several bacteria. Preliminary results revealed that the double bond at C-10 and the location of the orsellinic acid unit at C-6 in these

Appl Microbiol Biotechnol

azaphilones are pivotal to the antibacterial activity (Gao et al. 2011).

value of 31 nM, which is approximately 5-fold more potent than ciprofloxacin, was isolated (MIC=156 nM) (Zhao et al. 2013).

Algae Sponges Both extracellular and intracellular forms of the blue pigment named marennine produced by the diatom Haslea ostrearia manifested an antibacterial action, especially on the marine pathogen V. aesturianus. Marennine fixed on the gills of marine bivalves during filter feeding exerted a protective function. As a blue pigment marennine could also be utilized in food chemistry and engineering. Although it is ingested and possibly assimilated by green oyster consumers, it will have to go through a thorough assessment before use as a nutraceutical (Gastineau et al. 2012). The cholesterol derivative 24-propylidene cholest-5-en3β-ol from the seaweed Laurencia papillosa exhibited activity against four clinical isolates of Gram-negative bacteria (E. coli, P. aerugenosa, Klebsiella pneumoniae, and Shigella flexineri) with MICs ranging from 1.2 to 1.7 μg/ml (Kavita et al. 2013). Sulfated exopolysaccharides of microalgae effectively blocked adhesion of the human pathogen Helicobacter pylori to the HeLa S3 cell line, and adhesion of the fish pathogens Vibrio campbellii, V. ordalii, Streptococcus saprophyticus, and Aeromonas veronii to spotted sand bass primary tissue culture cells (Guzman-Murillo and Ascencio 2000). Carotenoids from microalgae are effective against Helicobacter pylori infection. Sulfated polysaccharides bear a prophylactic potential via blocking adhesion of pathogens to the gastric surface, H. pylori has been targeted as the primary cause of gastric cancer (Amaro et al. 2013). Cnidarians A madendrane-type sesquiterpenoid unique in the possession of a taurine group, (−)-4β-N-methenetauryl-10β-methoxy1β,5β,6α,7α-aromadendrane, was obtained from the gorgonian coral Melitodes squamata collected in South China Sea. The sesquiterpenoid exerted moderate inhibitory activity on B. subtilis and Micrococcus luteus (Huang et al. 2012). The methanol extract of Paracondactylis indicus showed a maximum inhibition zone of 9.7 mm against S. typhii and methanol and ethanol extracts of P. sinensis displayed a maximum inhibition zone of 9.8 mm against K. pneumonia. The methanol and ethanol extracts of Heteractis magnifica and Stichodactyla haddoni elicited a maximum inhibition zone of 10 mm against S. typhii and K. pneumonia (Subramanian et al. 2011). The active principles await chemical identification. From a gorgonian Carijoa sp. collected from the South China Sea, a new pregnane steroid that exhibited promising antibacterial activity against Pseudomona putida, with a MIC

Ethyl acetate extracts of the marine sponges Agelas oroides and Axinella damicornis collected from the Tunisian Mediterranean coast inhibited the growth of Pseudomonas aeruginosa and gentamycin-resistant strains of Listeria monocytogenese and Enterococcus feacalis as well as other bacteria (Ines et al. 2007). The active principles await identification. The synthetic proline-rich cyclopolypeptide stylisin 2 from the Jamaican sponge Stylissa caribica expressed potent antimicrobial activity against Pseudomonas aeruginosa and Klebsiella pneumonia, in addition to moderate antidermatophyte activity against pathogenic Trichophyton mentagrophytes and Microsporum audouinii compared with gatifloxacin and griseofulvin (Dahiya and Gautam 2010). Ageloxime B isolated from the marine sponge Agelas mauritiana is a diterpene alkaloid with anti-MRSA activity (Yang et al. 2012). Mass-directed isolation of the dichloromethane/methane extract of the marine sponge Suberea ianthelliformis revealed the bromotyrosine-derived metabolite ianthelliformisamine A which inhibited P. aeruginosa (PAO200 strain) with an IC50 value of 6.8 μM (MIC=35 μM) (Xu et al. 2012). Halistanol trisulfate (24ε,25-dimethylcholestane-2β,3α, 6α-triol trisodiumsulfate) isolated from the marine sponge Petromica citrina had a mode of action involving disruption of the cytoplasmic membrane with subsequent induction of cell lysis in exponentially growing S. aureus cells at the MIC (512 μg/ml). It exhibited moderate toxicity against Staphylococcus epidermidis, Enterococcus faecalis, Mycobacterium fortuitum, and Neisseria gonorrhoeae (Marinho et al. 2012). A bicyclic C(21) terpenoid, clathric acid, was isolated from the marine sponge Clathria compressa. It showed an MIC of 32 μg/ml against Staphylococcus aureus (ATTC 6538P) and 64 μg/ml against both methicillin-resistant (ATTC 33591) and vancomycin-resistant Staphylococcus aureus (VRSA) (Gupta et al. 2012). Seven new cyclic peptides callyaerins A-F and H containing ring systems of 5–9 amino acids and side chains of 2–5 amino acids in length from the sponge Callyspongia aerizusa showed biological activity in antibacterial assays (Ibrahim et al. 2010). A manzamine related alkaloid, zamamiphidin A, consisting of a new heptacyclic ring system has been isolated from an Okinawan marine sponge Amphimedon sp. The compound expressed anti-Staphylococcus aureus activity (MIC 32 μg/ml) (Kubota et al. 2013).

Appl Microbiol Biotechnol

Arthropods Sp-ALF, an antilipopolysaccharide factor from mud crab (Scylla paramamosain) hemocytes, which interacted with the bacterium V. parahaemolyticus, has also been isolated. Its isoforms manifested pronounced amino acid sequence homology with other crustacean ALFs. Both recombinant rSpALFs and sSp-ALFs were active against the majority of the Gram-positive and Gram-negative bacteria tested. Sp-ALFs did not affect E. coli by perturbing membrane integrity (Liu et al. 2012). T h e p e pt i d e s c y go n ad i n f r om th e c r a b S c yl l a paramamosain is probably involved in the regulation of reproductive immunity. E. coli-derived recombinant scygonadin exhibited more potent antibacterial activity than its Pichia pastoris-derived counterpart scygonadin. The antimicrobial activity of recombinant scygonadin against pathogenic Aeromonas hydrophila was not adversely affected by salt (Peng et al. 2012). This is a desirable feature of drug candidates for drug development. A unique isoform of antilipopolysaccharide factor (ALF) (PtALF7), identified from hemocyte complementary DNA (cDNA) library of the swimming crab Portunus trituberculatus, exerted antimicrobial activity against the tested Gram-negative and Gram-positive bacteria, but did not inhibit the growth of the fungus Pichia pastoris. After challenge with V. alginolyticus, which causes fatal infections in P. trituberculatus, the PtALF7 transcript expression in hemocytes declined at 6 h but rose at 24 h. The results indicate that PtALF7 is implicated in the innate immune response of P. trituberculatus (Liu et al. 2013). Table 2

Echinoderms Two new alkene sulfates, (5Z)-dec-5-en-1-yl sulfate and (3E)dec-3-en-1-yl sulfate, isolated from the sea cucumber Apostichopus japonicus, manifested activity against E. coli (La et al. 2012). Mollusks Marine snail (Hexaplex trunculus) hepatopancreatic phospholipase A(2) (mSDPLA(2)) demonstrated potent antibacterial activity against S. aureus and S. epidermidis (Zarai et al. 2012). The methanolic extract of the marine mollusk Melo melo, demonstrated antibacterial activity against S. aureus, Salmonella typhi, Salmonella paratyphi, Proteus mirabilis, V. p a r a h e m o l y t i c u s , a n d K l e b s i e l l a p n e u m o n i a (Sivasubramanian et al. 2011). The chemical structures of the active principles await elucidation. The decapeptides mytilin-derived-peptide-1 (MDP-1) and peptide-2 (MDP-2) are derived from residues 20–29 of

Properties of approved drugs originated form marine organisms Cytarabine /

Vidarabine

Trade name Origins

Cytosar-U Depocyt Tethya crypta (marine sponge)

Vira-A

Approval Date Uses

Omega -3-acid ethyl esters Lovaza

Ziconotide

Trabectedin

Prialt

Yondelis

Tethya crypta Fish especially oily (marine sponge) fish

Conus magus (cone snail)

1969 by FDA

1976 by FDA

2004 by FDA

2004 by FDA

Antitumor

Antivirus

Antihypertriglyceridemia

Analgesic

Ecteinascidia turbinate (sea squirt) 2007 by European Medicines Agency Antitumor

Eribulin mesylate Halaven

Adcetris

Iota carrageenan Carragelose

Halichodria okadai (sponge)

Dolabella auricularia (sea hare)

Rhodophyceae (red algae)

2010 by FDA

2011 by FDA

Antitumor

Antitumor

2008 in Austria as OTC drug Antivirus

It is a 25amino-acid peptide

Structure

Mechanism of Action

Gram-negative bacteria, often represented by Escherichia coli, have an anionic bacterial surface on which cationic chitosan derivatives interact electrostatically. Thus, many chitosan conjugates have cationic components such as ammonium, pyridinium, or piperazinium substituents introduced into their molecules to increase their positive charge. Gram-positive bacteria like Staphylococcus aureus are inhibited by the binding of lower molecular weight chitosan derivatives to DNA or RNA (Hayes et al. 2008; Jarmila and Vavrikova 2011).

It is a nucleoside and interferes with the cancer synthesis.

It is a nucleoside It is metabolized to omega. and interferes with the viral DNA synthesis.

It is an N-type voltage-gated calcium channel blocker

Brentuximab vedotin

It consists of (1) It is a mixture of chimeric monoclonal linear sulfated antibody brentuximab polysaccharides linked to (2)cathepsin cleavable linker, (3) para aminobenzylcarbamate spacer and (4) monomethyl auristatin E (MMAE). Not yet known; It is involved in the production superoxide near the DNA strand, resulting in DNA backbone cleavage and cell apoptosis

Cancer cell apoptosis following prolonged and irreversible mitotic blockade.

Its antibody portion is attached to the surface of tumor cells, delivering MMAE which is responsible for the anti-tumor activity.

It creates a protective physical anti-viral barrier in the nasal cavity.

Appl Microbiol Biotechnol

could be used as antibiotics (Lopez-Abarrategui et al. 2012). Tyrosinase is a copper-dependent enzyme reported from many dufferent organisms. It catalyzes phenol hydroxylation to catechols and catechol oxidation to quinones. The scallop (Chlamys farreri) tyrosinase cDNA encoded a protein composed of 486 amino acids. The expression level of its mRNA in hemocytes declined significantly during 3–6 h following lipopolysaccharide stimulation, and reached the lowest level at 6 h Furthermore, the antibacterial activity of the hemolymph against Escherichia coli was also elevated at 3 h after lipopolysaccharide stimulation, but fell upon treatment with a tyrosinase inhibitor. The data indicated that the scallop tyrosinase mediated immune response for annihilating pathogens in scallop (Zhou et al. 2012b).

mytilin-1 from Mytilus coruscus. The cationic peptides bound to the negatively charged bacterial wall by electrostatic interaction, disrupted the integrity of bacterial cell wall and cytoplasmic membrane, created pores, culminating in cell death. MDP-2 was more potent than MDP-1 in antibacterial activity due to different positive charge distribution of amino acids on the loop of the peptides (Yang et al. 2011). This report represents one of the very few mechanistic studies on marine antibacterial agents. Whether some of the other antibacterial agents referred to in the present article deploy an analogous antibacterial mechanism awaits elucidation. The Caribbean marine snail Cenchritis muricatus completely inhibited development of S. aureus and inhibited growth in Escherichia coli by 95.9 %. A 10-kDa protein and a 15-kDa protein were present. These proteins H

H

H

H

O

O

O

HO

O

H

H

H

H N

N H

O

OH

O

H

H NH O

H O

H

MC21-B (Isnansetyo and Kamei 2009)

O

NH

O H N

HO H

O

N

N H

O

macrolactin X (Mondol et al. 2013)

peptidolipins B (Wyche et al. 2012)

macrolactin Y (Mondol et al. 2013) H N

H2N HN

O

NH2

NH

O

O O

O

O

HN

H2N

NH O

NH

O N

H N O

macrolactin Z (Mondol et al. 2013)

O H2N

OH

O

O

NH2

O

mojavensin A (Ma et al. 2012)

Fig. 1 Structures of different marine products with antibacterial activities. a Marine products with antibacterial activities from marine bacteria. b Marine products with antibacterial activities from marine fungi. c Marine products with antibacterial activities from marine algae.

d Marine products with antibacterial activities from marine cnidarians. e Marine products with antibacterial activities from marine sponges. f Marine products with antibacterial activities from marine echinoderms

Appl Microbiol Biotechnol

Defensins and big defensins (cationic cysteine-abundant antimicrobial peptides) with antibacterial activity are produced by marine invertebrates including arthropods and mollusks echinoderms (Ng et al. 2013).

A 104-amino acid antibacterial protein with 10 cysteine residues designated as myticusin-1, synthesized and stored in circulating hemocytes of Mytilus coruscus, exhibited more potent activity against Gram-positive bacteria than Gramnegative bacteria and fungi. It elicited ultrastructural changes in Escherichia coli and Sarcina luteus. The expression level of myticusin-1 in hemocytes could be enhanced 20-fold following challenge with S. luteus (Liao et al. 2013). A 171-amino acid protein RpFeH from Manila clam (Ruditapes philippinarum) manifests an amino acid sequence with the characteristics of ferritin H subunits, including seven metal ligands in ferroxidase center, two iron-binding region signatures, and a potential biomineralization residue (Thy(27)). Recombinant RpFeH inhibited the growth of Vibrio tapetis. Transcriptional upregulation was observed in Manila clam gill tissue following infection with V. tapetis. RpFeH functions as an iron chelator in R. philippinarum and regulates the innate immune responses to bacterial infections, through its iron sequestering activity (Kim et al. 2012).

O

Fish The yolk protein vitellogenin was purified from the ovaries of amphioxus Branchiostoma belcheri tsingtauense which plays a role in defense reactions besides yolk protein formation in amphioxus (Zhang et al. 2005). Vitellogenins present in other animals are also defense proteins (Wu et al. 2015; Zhang et al. 2011). A mannose-specific tetrameric 180-kDa lectin from the ovaries of a teleost, the cobia Rachycentron canadum manifested antibacterial activity against Escherichia coli with 50 % inhibition at 250 μg (Ngai and Ng 2007). It is known that lectins from terrestrial organisms may have antibacterial activity (Lam and Ng 2011). Lectins from some marine worms

OH

O O

H

H N

N H

O

H

O

H

NH O

OH

kandenol A (Ding et al. 2012) O

O

OH

NH

HO H

OH

O H N

H O N

O

N H

O

peptidolipins E (Wyche et al. 2012)

OH

NH2

OH

kandenol B (Ding et al. 2012) O

OH

OH O H N

HO

O

H N

OH

O

H N

N H

OH

N H

O

kandenol C (Ding et al. 2012)

O

O

O

O O

OH

O

NH O

OH

O N

O

OH

OH

O

O

O

kandenol D (Ding et al. 2012) O

HN H N

H

N H

OH

O

O

NH2

O

HO

fengycin B (Ma et al. 2012)

kandenol E (Ding et al. 2012) O

O OHC

O

N

N HO

O

OH

H3C

pseudonocardians A (Li et al. 2011)

Fig. 1 (continued)

H N

N H OH

O

O

O

O COOH

antimycin B2 (Han et al. 2012)

Appl Microbiol Biotechnol

demonstrated salt sensitivity with abrogation of activity at physiological salt concentrations which is regarded as an undesirable feature for drug development that awaits improvement/rectification by altering the amino acid sequence. In low ionic strength medium, activity against marine and nonmarine Gram-negative bacteria with an MIC of 10 μM, and weak activity against a Gram-positive bacterium (MIC=80 μM) were present. The cod cathelicidin caused bacteria to undergo lysis. Cleavage of the peptide into fragments resulted in abolition of its antibacterial activity (Broekman et al. 2011). Synthetic rainbow trout cathelicidins rtCATH 1 and rtCATH 2 displayed high antimicrobial potency. Constitutive expression of rtCATH 2 was detected in the head kidney, gills, spleen, intestine, and skin, whereas rtCATH 1 expression in the head kidney, gills, and spleen was inducible following challenge with bacteria (Chang et al. 2006).

and plants exhibit anti-HIV activity (Akkouh et al. 2015). Whether fish lectins have anti-HIVactivity remains to be seen. Cathelicidins are antimicrobial peptides which regulate innate immunity in mammals. They are cationic host defense peptides which share a conserved DNA and preproprotein sequence at the N-terminal which displays pronounced similarity to that upstream of the coding sequence for cathelin, a cathepsin L protease inhibitor from pig neutrophils. Potential protease inhibitory activity of cathelicidins has seldom been studied and the major focus of research is on its anti-infective, anticancer, and immunomoduatory activities. All cathelicidins possess a highly homologous N-terminal preproprotein sequence followed by a heterogeneous C-terminal mature peptides. Cathelicidins have been reported from various mammalian species, and a few species each of avians, reptiles, and amphibians. Findings on fish cathelicidins are limited. Novel mature cathelicidin peptide (codCath) from Atlantic cod O

O

N

N

O

NH2

HN

CH2

H2C

OH

HO

O

O

H3CH2C

O NH

pseudonocardians B (Li et al. 2011) O N HN

H2C O HO

N

N H

O

NH

OO OH

S

OH

N

OH

N

pseudonocardians C (Li et al. 2011) R1

O

O N

1

R2

R

H

CH2CH3

Nocapyrone F

H

CH3

Nocapyrone G

OH

CH2CH3

NH2 N

N

S

S

O

O

NH

O

N

O

O OCH3

Cl

N

HN

nocapyrones E-G (Fu et al. 2011a) H N

O

S

N

H N

R2

Nocapyrone E

CH3

O

O

S Cl

PM181104 (Mahajan et al. 2013) N H

O

N H

lynamicin A (McArthur et al. 2008)

NH

O

O

lipoxazolidinone A (Sunga et al. 2008)

Fig. 1 (continued)

OH

Appl Microbiol Biotechnol

The rockfish (Sebastes schlegeli) skin mucus contains a potent antibacterial L-amino acid oxidase with strict substrate specificity that acted against water-borne Gram-negative bacteria (Kitani et al. 2013). The cDNA sequence of tilapia viperin coding for the conserved domain of radical S-adenosylmethionine superfamily proteins demonstrated homology to those of several fish viperins in GenBank like viperins of Coreoperca whiteheadi, C. kawamebari, and Sciaenops ocellatus. Tilapia viperin expression was upregulated in various organs upon lipopolysaccharide challenge and poly(I:C), and injection of S t re p t o c oc c u s ag a l a c t i ae an d Vib ri o v ul n ifi c us . Electrotransfer of a plasmid expressing viperin into muscles of zebrafish led to a reduction in bacterial count and changes in expression of immune-associated genes suggesting that viperin exerts an antibacterial action (Lee et al. 2013). Galectins are galactose-binding proteins that play crucial roles including bactericidal and anticancer function (Arthur et al. 2015; Yau et al. 2015). Galectin-3 binding protein from half-smooth tongue sole (Cynoglossus semilaevis) is composed of 565 amino acids and possesses a scavenger receptor cysteine-rich domain with three intramolecular disulfide

Atlantic salmon cathelicidin 1 and 2 activated peripheral blood leukocytes, upregulating interleukin-transcription 8, and displayed a direct killing effect on E. coli as well as the fish pathogen Vibrio anguillarum (Bridle et al. 2011). Cathelicidin expression in a gadoid and a salmonid cell line was induced after stimuli with microorganisms. Pattern recognition receptors such as toll-like receptor 5 are possibly implicated in salmonids in the upreglation of cathelicidin expression and the signalling cascade can comprise phosphatidylinositol-3-kinase and cellular trafficking compartments. Knowledge of the factors regulating AMP-related defence responses, including cathelicidin, could help in developing strategies to enhance the immune defence of fish (Broekman et al. 2013). Whether cod and salmonid cathelicidins display antifungal and antiviral activities as shown by mammalian cathelicidins (Wong et al. 2011a, b) awaits investigation. L-Amino acid oxidases are found in many organisms and catalyze oxidative deamination of L-amino acids to α-keto acids and ammonia. They display different activities one of which is antimicrobial activity (Hossain et al. 2014). O

H N

OCH3

Cl

CH3

Cl

Cl

N

O

N H

N H

lynamicin B (McArthur et al. 2008)

HO

H N

H3CO

H N

NH

Cl

O S

N H

N

N H

S

S

H

O

N

H NH2 O

O

nosiheptide (Haste et al. 2012)

O OCH3

H N

N

N H

OH

S

lynamicin C (McArthur et al. 2008) O

N

O

S

O N H

NH O

CH3

Cl

Cl

CH3

HO H

S

H

O

Cl

Cl

HN

H N

NH2

N

Cl

1(10-aminodecyl) pyridinium (Dasari et al. 2012) N H

N

N

N H

lynamicin D (McArthur et al. 2008)

O xinghaiamine (Jiao et al. 2013) OH O

caerulomycin A (Fu et al. 2011b)

H3COOC

caerulomycin C (Fu et al. 2011b)

O

O

OH

O

fradimycins A (Xin et al. 2012)

Fig. 1 (continued)

OH

HO OH

O

O

O

O

Appl Microbiol Biotechnol

GFAVGMAAGAMFGTFSCLR and displaying pronounced homology with mammalian orthologues. Hepatic glyrichin transcripts were upregulated in healthy rock bream exposed to Streptococcus iniae and Edwardsiella tarda The synthetic peptide (pOf19) demonstrated activity against the bacteria E. coli, E. tarda, and S. iniae and induced membrane lysis (Kasthuri et al. 2013). Half-smooth tongue sole (Cynoglossus semilaevis) interferon regulatory factor 1 (IRF1) was conserved in the teleost evolutionary branch which was independent of those of mammals and other submammalian vertebrates. CsIRF1 exhibited striking homology to counterparts from other marine fishes and less pronounced resemblance to freshwater fishes. Its gene expression in the liver was upregulated by infections of Vibrio anguillarum. CsIRF1 might be involved in Cynoglossus semilaevis innate defense against bacteria (Lu et al. 2014). Antimicrobial proteins and peptides with various structural features are produced by a host of terrestrial and marine

bonds. The protein was expressed in a diversity of tissues and was upregulated after bacterial and megalocytiviral infection when it appeared in the serum and in the culture medium of peripheral blood leukocytes. The purified recombinant protein displayed stronger binding to Gram-negative bacteria than to Gram-positive bacteria (Chen et al. 2013). C-reactive protein (CRP), the major human acute phase protein, is a member of the pentraxin family which are evolutionarily conserved proteins involved in innate immunity. CRP from half-smooth tongue sole (Cynoglossus semilaevis) has 228 amino acid residues and a Pentraxin/CRP domain. Expression of CsCRP was upregulated in the blood, liver, kidneys, and spleen following infection. Purified recombinant CsCRP (rCsCRP) interacts with Gram-negative and Grampositive bacteria. The respiratory burst and phagocytic capacity of peripheral blood leukocytes infected with bacteria were elevated by rCsCRP (Li et al. 2013). Glyrichin is a 79-amino-acid antibacterial transmembrane protein with a transmembrane domain at GFMM O

OH

OH

Cl

O

O

OH

1

HO OC

OH

O

O

O

O

O

OH OH

O

O

O

fradimycins B (Xin et al. 2012) OH O

4dehydro-4a-dechlorona pyradiomycin A1 (1) (Wu et al. 2013) Cl

R1

O

OH

O

O HO OC

O

OH

O

O

MK844-mF10 (Xin et al. 2012)

2 R1 = Br, R2 = CH3 4 R1 = Cl, R2 = CH3 5 R1 = Cl, R2 = CHO

S O S

N N

NH

R2

3-dechloro-3-bromonapyradiomycin A1 (2), napyradiomycin A1 (3) and 18oxonapyradiomycin A1 (4) (Wu et al. 2013) O

N

N

S

O

OH O

O NH

OH

Cl

3

3-chloro-6, 8-dihydroxy-8-α-lapachone (3) (Wu et al. 2013)

Fig. 1 (continued)

S

N H

OH

OH OH

O

O

O

O

marthiapeptide A (Zhou et al. 2012)

O

Appl Microbiol Biotechnol

organisms alike to combat microbial invasion and protect against infection caused by these pathogens. Hepcidin is a cysteine-rich fish peptide with antimicrobial and antitumor activities. The C-hepcidin3 gene was cloned from the o r a n g e - s p o t t e d g r o u p e r ( E p i n e p h e l u s c o i o id e s ) . Recombinant EC-proHep3 acted speedily against Pseudomonas stutzeri and Staphylococcus aureus (Qu et al. 2013). SmHep1P and SmHep2P, two turbot (Scophthalmus maximus) hepcidins with about 50 % sequence identity, play a role in regulation of iron homeostasis and antibacterial defense. SmHep1P and SmHep2P exhibited higher activity

O

Cl

Cl

toward Gram-positive bacteria and Gram-negative bacteria, respectively. They bound to the bacteria and changed the surface structures, decreased bacterial invasion into fish cells in vitro, and augmented resistance against viruses and bacteria in vivo. SmHep2P manifested more potent antimicrobial activities than SmHep1P (Zhang et al. 2014a). A chicken-type (c-type) lysozyme (SmLysC) was isolated from Scophthalmus maximus. Bacterial infection evoked expression of SmLysC in the head kidney, spleen, and liver in a time-dependent manner. Gram-positive bacteria exhibited greater sensitivity to recombinant SmLysC (rSmLysC) than Gram-negative bacteria. Thus SmLysC is a functional

OH

O OH O

O

OH

H

O

Cl

OH

HN

HO

napyradiomycin B1(6) and napyradiomycin B3 (7) (Wu et al. 2013) Cl

O

O

R

O

O

O

6 R = Cl 7 R = Br

R1 O

O

O

H

OH

H

O O

O

H

O

O

OH

O

O

9

R2

napyradiomycin SR (Wu et al. 2013) R

O

O

2 R1 = NO2, R2 = CHO 4 R1 = NO2, R2 = CH2OH 5 R1 = NH2, R2 = CH2OH

O

lobophorins 2, 4 and 5 (Lin et al. 2014) OH

O

HO

O O

1R=H 2 R = OH

O

O

OH

O

marfuraquinocins A (1) and C (2) (Song et al. 2013)

O

H

3

O

O O

HO

O O

marfuraquinocin D (Song et al. 2013)

Fig. 1 (continued)

H

O NO2

O

H

OH

O

HN

HO

O

OH O

lobophorins 3 (Lin et al. 2014)

Appl Microbiol Biotechnol

lysozyme probably involved in immune defense against extracellular bacterial pathogens, especially Gram-positive bacteria (Yu et al. 2013). Epinecidin-1 (Huang et al. 2013; Lin et al. 2013; Pan et al. 2007, 2011) and pleurocidin (Choi and Lee 2012; Souza et al. 2013) are antibacterial peptides from groupers and flatfish which are active even in the truncated form. Reptiles Defensins are cationic cysteine-rich host defense peptides previously reported from vertebrates, invertebrates, plants, and fungi (Ng et al. 2013). A 36-amino-acid cationic

antibacterial peptide with six half-cysteines and a threedimensional structure analogous to vertebrate betadefensins was found in the egg white of the marine turtle Caretta caretta. However, the S-S linkages at C1-C6/C2C5/C3-C4 were at different locations compared with those in vertebrate beta-defensins. The protein manifested potent inhibitory activity against the bacteria Escherichia coli and Salmonella typhimurium. There is no lysozyme in the egg white whose antimicrobial role has been taken over by the peptide (Chattopadhyay et al. 2006). Future investigations may reveal whether reptile defensins also display antifungal and antiviral activities as in defensins from mammals.

O RO

O

O N H

O

N O O

O

1 R = Ac 2R =H nocardiopyrones A(1) andB (2) (W ang et al. 2013b)

O N

O

O

O

O

N N

N H

pitiprolamide(Montaser et al. 2011) OH

a

marine products with antibacterial activities from marine bacteria O

O

OH O

O

O

OH

O

toluhydroquinone(Leutou et al. 2012)

6,8-di-O-methylaverufin(Miao et al. 2012)

OH

OH

O

OH

HO

O OH

O

gentisyl alcohol(Leutou et al. 2012)

O O

HO

6-O-methylaverufin(Miao et al. 2012) O

H

OH

H

O

OH

HO

H OH

(-)-sydonol (Li et al. 2012) OH HO

ergosteroid 1(Zheng et al. 2013)

Fig. 1 (continued)

Appl Microbiol Biotechnol

Clinical studies of marine natural products

have been approved as prescription drugs and one as an overthe-counter (OTC) drug. Their details are listed in Table 2. However, all the aforementioned drugs are for antitumor, antivirus, and analgesic purposes. However, there is still a number of bioactive molecules from marine species that have been selected for preclinical development as antimicrobials, including manzamine A isolated from the sponge Acanthostrongylophora sp. (antituberculosis) (EspinozaMoraga et al. 2013) and psammaplin A isolated from another sponge Psammaplysilla (antibacterial) (Laport et al. 2009).

Many bioactive molecules from marine organisms have been proven to be antibacterial (as described in this review), antifungal, antiviral (Cheung et al. 2014), antitumor (von Schwarzenberg and Vollmar 2013), and antiallergic (Vo et al. 2014) agents. These compounds could be used in the unmodified form or provide lead structures for potential drug candidates. There are a huge number of bioactive molecules isolated from marine species out of a probable total of one million compounds (Bhatnagar and Kim 2012), but only a minute portion of these molecules has been approved for the clinical trial stage and even less reached the drug market. Those which have entered clinical trials included alpidin, bryostatin 1, didemnin B, dehydrodidemnin B, dolastatin 10, discodermolideand, kahalalide F, and manoalide (Kijjoa and Sawangwong 2004). To the best of our knowledge, only seven

Conclusion The rapid rise in antimicrobial resistance in bacteria has generated an increased demand for the development of novel therapies to treat contemporary infections. In an ongoing

(-)-sydonic acid (Li et al. 2012) HO H

OH

aspergiterpenoid A (Li et al. 2012)

H

HO

HO

O

O

H

3β-hydroxyergosta-8,24(28)-dien-7-one (Zheng et al. 2013)

OH

(-)-5-(hydroxymethyl)-2-(2',6',6'trimethyltetrahydro-2H- pyran-2-yl)phenol (Li et al. 2012) O

H

OH

HO O

HO

HO

H

CH3

O

7-nor-ergosterolide (Zheng et al. 2013)

O O

coniothranthraquinone 1 (Khamthong et al. 2012) OH

H

O

OH

O HO OH

O

emodin (Khamthong et al. 2012) OH

O

O O

O

O R

O O

Calcaride A, R = H:

O

OH O

Calcaride B, R = OH

calcaride A and B (Silber et al. 2013) H N O O N H

H

N H

cristatumins A (Du et al. 2012)

Fig. 1 (continued)

OH

Appl Microbiol Biotechnol

fish, they express a very wide range of compounds including proteins, polypeptides, and diterpenes. The varieties of chemical structures displayed by antibacterial compounds of marine origins are depicted in Fig. 1. Moreover, many of them are structurally different from antibiotics derived from terrestrial organisms. Some antibacterial dithiolopyrrolone derivatives have demonstrated promising antitumor activities (Qin et al. 2013). NKLP27 antibacterial peptide from tongue sole also has antiviral activity (Zhang et al. 2014b). Gageostatins, antibacterial lipopeptides from a marine Bacillus subtilis, display antiviral, antifungal, and cytotoxic activities (Tareq et al. 2014). Whether these marine antibacterial products possess other biological actvities remains to be seen. The mechanisms of action of some of the marine antibacterial proteins and compounds have been disclosed. The antimycobacterial activity of trichoderins, aminolipopeptides from the culture of the marine spongederived fungus Trichoderma sp., was associated with the suppression of ATP synthesis (Pruksakorn et al. 2011).

study to develop new antibacterial agents against antibioticresistant bacteria, marine natural products have attracted much attention to provide a novel insight into developing potential and useful antimicrobial agents since more bacteria are becoming resistant to antibiotics. Antibacterial proteins and compounds are produced by terrestrial organisms including invertebrates (Herbiniere et al. 2005; Porto et al. 2014; Wilmes et al. 2011), vertebrates (Costa et al. 2014; Wilmes et al. 2011; Wong et al. 2013; Yin et al. 2014), plants (da Silva Dantas et al. 2014; Ngai and Ng 2004; Wilmes et al. 2011; Wong et al. 2006; Ye et al. 2011), mushrooms (Zheng et al. 2010), fungi (Wilmes et al. 2011), and bacteria (Li et al. 2014; Troskie et al. 2014; Wilmes et al. 2011). It has been reported that compounds derived from marine organisms are structurally diverse and also differ from natural products identified from terrestrial organisms (Trujillo et al. 2007; Woodford 2005). As is evident from this brief survey of antibacterial agents from marine organisms including bacteria, fungi, algae, invertebrates, and OH

O H N O

O

O

OH

O N H

HO

O O

O

O

O

O

OH

N H

O

O OH

calcaride C (Silber et al. 2013)

cristatumins B (Du et al. 2012) O

O

H2N

O

N H

O

H O C8H17

N H

N

R1

O N H

H N

O

O

O

R2

OH

O

H N

N H

O

H N O

O

1

R2 = CH3

R =

Trichderin A

OH

N H

O

cristat

umins D (Du et al. 2012) O

O

H N

N H

O

OH

Trichderin A1

R1 =

Trichderin B

R1 =

R2 = CH3 OH

OH O

isorhodoptilometrin-1-methyl ether (Hawas et al. 2012) O

O

O

R2 = H

trichderin A, A1 and B (Pruksakorn et al. 2010) H N

O

O HN NH

O

siderin (Hawas et al. 2012)

O N H

fellutanine (Schulz et al. 2011)

Fig. 1 (continued)

N

OH

Appl Microbiol Biotechnol OH

O

HO

O

COOH

O

COOH

O

spiculisporic acid B (Wang et al. 2012)

penicifuran A (Qi et al. 2013) OH

O

O

O

COOCH3

OH O O

COOH

O

spiculisporic acid C (Wang et al. 2012) O

H HO

O

COOH

Penicitrinol J (Wang et al. 2013a) OH

O

COOH

OH

spiculisporic acid D (Wang et al. 2012) O

O OH O

HO O

O

H

Penicitrinol K (Wang et al. 2013a)

H

HO

OCH3

O

OH

comazaphilones C (Gao et al. 2011)

b

marine products with antibacterial activities from marine fungi H

H H H

H

HO

24-propylidene cholest- 5-en-3β-ol (Kavita et al. 2013)

c

marine products with antibacterial activities from marine algae

Fig. 1 (continued)

Mytilin-derived peptide-1 and mytilin-derived peptide-2, truncated decapeptides with reversed sequence synthesized corresponding to the residues 20–29 of M. coruscus mytilin1 (GenBank accession no. FJ973154), bound to the negatively charged bacterial wall by electrostatic attraction, made pores in the bacterial membrane, and thus killed the bacteria. Transmission electron microscopic investigations disclosed similar bactericidal mechanisms toward E. coli and S. lutea (Yang et al. 2011). Phlorofucofuroeckol-A isolated from the edible brown alga Eisenia bicyclis significantly suppressed the expression of the methicillin resistance mecI, mecR1, and mecA associated genes and production of penicillinbinding protein 2a (Eom et al. 2014). NKLP27 peptide from tongue sole (Cynoglossus semilaevis) permeabilized bacterial

cell membrane and degraded genomic DNA. Treatment of tongue sole with NKLP27 prior to bacterial and viral infection minimized the spread and replication of the bacteria and virus in the fish tissues and augmented expression of the immune defense genes (Zhang et al. 2014b). Holomycin from marine bacteria inhibited rifamycin-resistant bacteria and methicillinresistant Staphylococcus aureus N315 by suppressing RNA synthesis. Yersinia ruckeri, a piscine pathogen, used RNA methyltransferase for self-resistance during holomycin production (Qin et al. 2013). The mechanisms of many other antibacterial products of marine origin await elucidation and novel and exploitable mechanisms may be unraveled in future investigations. The prospects of employing these biomolecules in clinical practice to combat antibiotic-

Appl Microbiol Biotechnol H3COC

H

SO3H

N H

H H

H

H

H

OH

O

(-)-4β-N-methenetauryl-10β-methoxy-1β,5β,6α,7αaromadendrane (Huang et al. 2012)

15β-hydroxypregna-1,4,20-trien-3-one (Zhao et al. 2013)

d marine products with antibacterial activities from marine cnidarians HN

O H N

N

N O

HN

N

HO

N

N

O N H O

stylisin 2 (Dahiya and Gautam 2010)

H

O OH

ageloxime B (Yang et al. 2012) Br

H

O

clathric acid (Gupta et al. 2012)

H N

Br

H N

N H

NH2

O

ianthelliformisamines A (Xu et al. 2012)

H O H N

N

NaO3SO

H NaO3SO

H

OSO3Na

H

halistanol trisulphate (Marinho et al. 2012)

zamamiphidin (Kubota et al. 2013)

d

marine products with antibacterial activities from marine sponges

OSO3 (5Z)-Dec-5-en-1-yl sulfate (La et al. 2012)

e

OSO3 (3E)-Dec-3-en-1-yl sulfate (La et al. 2012)

marine products with antibacterial activities from marine echinoderms

Fig. 1 (continued)

resistant strains, in agriculture and in the food industry are promising in view of the wealth of these compounds from marine organisms. As the interest in marine antibacterial products first started in the 1970s, after 40 years of investigations which is not an excessively long period for drug development, it is expected that a number of marine antibacterials will proceed to the preclinical or clinical stage in the near future.

Although the mechanisms of antifungal and antiviral activities of only some of the aforementioned marine antibacterial biomolecules have been elucidated, the possibility to apply those with distinctly different mechanisms, good bioavailability, and minimal toxicity in combination therapy remains to be examined. It is also worthwhile to test the marine antimicrobials for possible synergism with existing drugs. During the last 50 years, over 9000 papers have reported the isolation of

Appl Microbiol Biotechnol

over 20,000 novel marine natural products. These new products came from just over 2500 species when compared with approximately 200,000 species in the marine habitat (Blunt et al. 2015). The collection of samples of marine species and the studies of their natural products were usually conducted randomly in shallow coastal areas in the past. The untapped marine environment with its novel microflora remains a comparatively undiscovered source of bioactive molecules and they are waiting to be discovered. Currently, with the use of sophisticated equipment like submarine or remotely operated vehicles, we can explore the otherwise inaccessible environment. However, such sampling equipments are very exclusive and owned only by a few well-funded laboratories, besides the major biological diverse marine habitats are located in developing countries from the tropical and subtropical regions (Dias et al. 2012). International collaborations and investments from pharmaceutical industries are thus imperative in the development process. Acknowledgments We gratefully acknowledge the award of an RFCI D research grant (no. 10090812) from Food and Health Bureau, The Government of Hong Kong Special Administrative Region, direct grants 4054049 and 4054135 from Medicine Panel, Research Committee, the Chinese University of Hong Kong, and grant from the National Natural Science Foundation of China (nos. 81201270 and 81273275). Conflict of interest The authors declare no conflict of interest.

References Akkouh O, Ng TB, Singh SS, Yin C, Dan X, Chan YS, Pan W, Cheung RC (2015) Lectins with anti-HIV activity: a review. Molecules 20(1):648–668. doi:10.3390/molecules20010648 Amaro HM, Barros R, Guedes AC, Sousa-Pinto I, Malcata FX (2013) Microalgal compounds modulate carcinogenesis in the gastrointestinal tract. Trends Biotechnol 31(2):92–98. doi:10.1016/j.tibtech. 2012.11.004 Ammerman JW, Fuhrman JA, Hagstrom A, Azam F (1984) Bacterioplankton growth in seawater: I. Growth kinetics and cellular characteristics in seawater cultures. Mar Ecol-Prog Ser 18(1–2):31– 39. doi:10.3354/meps018031 Aneiros A, Garateix A (2004) Bioactive peptides from marine sources: pharmacological properties and isolation procedures. J Chromatogr B Analyt Technol Biomed Life Sci 803(1):41–53. doi:10.1016/j. jchromb.2003.11.005S1570023203009255 Annamalai N, Kumar A, Saravanakumar A, Vijaylakshmi S, Balasubramanian T (2011) Characterization of protease from Alcaligens faecalis and its antibacterial activity on fish pathogens. J Environ Biol 32(6):781–786 Arthur CM, Cummings RD, Stowell SR (2015) Evaluation of the bactericidal activity of galectins. Methods Mol Biol 1207:421–430. doi: 10.1007/978-1-4939-1396-1_27 Bachmann BO, Van Lanen SG, Baltz RH (2014) Microbial genome mining for accelerated natural products discovery: is a renaissance in the making? J Ind Microbiol Biotechnol 41(2):175–184. doi:10.1007/ s10295-013-1389-9 Barboza NM, Medina DJ, Budak-Alpdogan T, Aracil M, Jimeno JM, Bertino JR, Banerjee D (2012) Plitidepsin (aplidin) is a potent

inhibitor of diffuse large cell and Burkitt lymphoma and is synergistic with rituximab. Cancer Biol Ther 13(2):114–122. doi:10.4161/ cbt.13.2.18876 Bassetti M, Merelli M, Temperoni C, Astilean A (2013) New antibiotics for bad bugs: where are we? Ann Clin Microbiol Antimicrob 12:22. doi:10.1186/1476-0711-12-22 Bergmann W, Feeney RJ (1950) The isolation of a new thymine pentoside from sponges. J Am Chem Soc 72(6):2809–2810. doi: 10.1021/ja01162a543 Bergmann W, Feeney RJ (1951) Contributions to the study of marine products XXXII. The nucleosides of sponges. I. J Org Chem 16(6):981–987. doi:10.1021/jo01146a023 Bhatnagar I, Kim SK (2010) Immense essence of excellence: marine microbial bioactive compounds. Mar Drugs 8(10):2673–2701. doi: 10.3390/md8102673 Bhatnagar I, Kim SK (2012) Pharmacologically prospective antibiotic agents and their sources: a marine microbial perspective. Environ Toxicol Pharmacol 34(3):631–643. doi:10.1016/j.etap.2012.08.016 Blunt JW, Copp BR, Keyzers RA, Munro MHG, Prinsep MR (2015) Marine natural products. Nat Prod Rep 32(2):116–211. doi:10. 1039/c4np00144c Boucher HW, Talbot GH, Benjamin DK, Bradley J, Guidos RJ, Jones RN, Murray BE, Bonomo RA, Gilbert D, Amer IDS (2013) 10 × ’20 Progress-development of new drugs active against Gram-negative Bacilli: an update from the infectious diseases society of America. Clin Infect Dis 56(12):1685–1694. doi:10.1093/Cid/Cit152 Bridle A, Nosworthy E, Polinski M, Nowak B (2011) Evidence of an antimicrobial-immunomodulatory role of Atlantic salmon cathelicidins during infection with Yersinia ruckeri. PLoS ONE 6(8):e23417. doi:10.1371/journal.pone.0023417PONE-D-1110331 Broekman DC, Zenz A, Gudmundsdottir BK, Lohner K, Maier VH, Gudmundsson GH (2011) Functional characterization of codCath, the mature cathelicidin antimicrobial peptide from Atlantic cod (Gadus morhua). Peptides 32(10):2044–2051. doi:10.1016/j. peptides.2011.09.012 Broekman DC, Guethmundsson GH, Maier VH (2013) Differential regulation of cathelicidin in salmon and cod. Fish Shellfish Immunol 35(2):532–538. doi:10.1016/j.fsi.2013.05.005 Burkholder PR, Ruetzler K (1969) Antimicrobial activity of some marine sponges. Nature 222(5197):983–984 Carter GT (2011) Natural products and Pharma 2011: strategic changes spur new opportunities. Nat Prod Rep 28(11):1783–1789. doi:10. 1039/c1np00033k Chang CI, Zhang YA, Zou J, Nie P, Secombes CJ (2006) Two cathelicidin genes are present in both rainbow trout (Oncorhynchus mykiss) and Atlantic Salmon (Salmo salar). Antimicrob Agents Chemother 50(1):185–195. doi:10.1128/aac. 50.1.185-195.2006 Chattopadhyay S, Sinha NK, Banerjee S, Roy D, Chattopadhyay D, Roy S (2006) Small cationic protein from a marine turtle has betadefensin-like fold and antibacterial and antiviral activity. Proteins 64(2):524–531. doi:10.1002/Prot.20963 Chen C, Chi H, Sun BG, Sun L (2013) The galectin-3-binding protein of Cynoglossus semilaevis is a secreted protein of the innate immune system that binds a wide range of bacteria and is involved in host phagocytosis. Dev Comp Immunol 39(4):399–408. doi:10.1016/j. dci.2012.10.008 Cheung RC, Wong JH, Pan WL, Chan YS, Yin CM, Dan XL, Wang HX, Fang EF, Lam SK, Ngai PH, Xia LX, Liu F, Ye XY, Zhang GQ, Liu QH, Sha O, Lin P, Ki C, Bekhit AA, Bekhit Ael D, Wan DC, Ye XJ, Xia J, Ng TB (2014) Antifungal and antiviral products of marine organisms. Appl Microbiol Biotechnol 98(8):3475–3494. doi:10. 1007/s00253-014-5575-0 Chin YW, Balunas MJ, Chai HB, Kinghorn AD (2006) Drug discovery from natural sources. AAPS J 8(2):E239–E253. doi:10.1208/ aapsj080228

Appl Microbiol Biotechnol Choi H, Lee DG (2012) Antimicrobial peptide pleurocidin synergizes with antibiotics through hydroxyl radical formation and membrane damage, and exerts antibiofilm activity. Biochim Biophys Acta 1820(12):1831–1838. doi:10.1016/j.bbagen.2012.08.012 Costa WK, Souza EL, Beltrao-Filho EM, Vasconcelos GK, SantiGadelha T, de Almeida Gadelha CA, Franco OL, Magnani M (2014) Comparative protein composition analysis of goat milk produced by the Alpine and Saanen breeds in northeastern Brazil and related antibacterial activities. PLoS ONE 9(3):e93361. doi:10. 1371/journal.pone.0093361PONE-D-13-42813 Culligan EP, Sleator RD, Marchesi JR, Hill C (2014) Metagenomics and novel gene discovery: promise and potential for novel therapeutics. Virulence 5(3):399–412. doi:10.4161/viru.27208 da Silva Dantas CC, de Souza EL, Cardoso JD, de Lima LA, de Sousa Oliveira K, Migliolo L, Dias SC, Franco OL, Magnani M (2014) Identification of a napin-like peptide from Eugenia malaccensis L. seeds with inhibitory activity toward Staphylococcus aureus and Salmonella Enteritidis. Protein J. doi:10.1007/s10930-014-9587-5 Dahiya R, Gautam H (2010) Total synthesis and antimicrobial activity of a natural cycloheptapeptide of marine origin. Mar Drugs 8(8):2384– 2394. doi:10.3390/Md8082384 Darabpour E, Ardakani MR, Motamedi H, Ronagh MT, Najafzadeh H (2012) Purification and optimization of production conditions of a marine-derived antibiotic and ultra-structural study on the effect of this antibiotic against MRSA. Eur Rev Med Pharmacol Sci 16(2): 157–165 Dasari VRRK, Muthyala MKK, Nikku MY, Donthireddy RR (2012) Novel pyridinium compound from marine actinomycete, Amycolatopsis alba var. nov DVR D4 showing antimicrobial and cytotoxic activities in vitro. Microbiol Res 167(6):346–351. doi:10. 1016/j.micres.2011.12.003 Dias DA, Urban S, Roessner U (2012) A historical overview of natural products in drug discovery. Metabolites 2(2):303–336. doi:10.3390/ metabo2020303 Ding L, Maier A, Fiebig HH, Lin WH, Peschel G, Hertweck C (2012) Kandenols A-E, eudesmenes from an endophytic Streptomyces sp of the mangrove tree Kandelia candel. J Nat Prod 75(12):2223–2227. doi:10.1021/Np300387n Donia M, Hamann MT (2003) Marine natural products and their potential applications as anti-infective agents. Lancet Infect Dis 3(6):338– 348. doi:10.1016/S1473-3099(03)00655-8 Du FY, Li XM, Li CS, Shang Z, Wang BG (2012) Cristatumins A-D, new indole alkaloids from the marine-derived endophytic fungus Eurotium cristatum EN-220. Bioorg Med Chem Lett 22(14):4650– 4653. doi:10.1016/j.bmcl.2012.05.088 Dusane DH, Matkar P, Venugopalan VP, Kumar AR, Zinjarde SS (2011) Cross-species induction of antimicrobial compounds, biosurfactants and quorum-sensing inhibitors in tropical marine epibiotic bacteria by pathogens and biofouling microorganisms. Curr Microbiol 62(3): 974–980. doi:10.1007/s00284-010-9812-1 El-Sersy NA, Abdelwahab AE, Abouelkhiir SS, Abou-Zeid DM, Sabry SA (2012) Antibacterial and anticancer activity of epsilon-poly-Llysine (epsilon-PL) produced by a marine Bacillus subtilis sp. J Basic Microbiol 52(5):513–522. doi:10.1002/jobm.201100290 Eom SH, Lee DS, Jung YJ, Park JH, Choi JI, Yim MJ, Jeon JM, Kim HW, Son KT, Je JY, Lee MS, Kim YM (2014) The mechanism of antibacterial activity of phlorofucofuroeckol-A against methicillinresistant Staphylococcus aureus. Appl Microbiol Biotechnol 98(23):9795–9804. doi:10.1007/s00253-014-6041-8 Espinoza-Moraga M, Njuguna NM, Mugumbate G, Caballero J, Chibale K (2013) In silico comparison of antimycobacterial natural products with known antituberculosis drugs. J Chem Inf Model 53(3):649– 660. doi:10.1021/ci300467b Fenical W (1993) Chemical studies of marine-bacteria—developing a new resource. Chem Rev 93(5):1673–1683. doi:10.1021/ Cr00021a001

Flemer B, Kennedy J, Margassery LM, Morrissey JP, O’Gara F, Dobson ADW (2012) Diversity and antimicrobial activities of microbes from two Irish marine sponges, Suberites carnosus and Leucosolenia sp. J Appl Microbiol 112(2):289–301. doi:10.1111/j. 1365-2672.2011.05211.x Fu P, Liu P, Qu H, Wang Y, Chen D, Wang H, Li J, Zhu W (2011a) Alphapyrones and diketopiperazine derivatives from the marine-derived actinomycete Nocardiopsis dassonvillei HR10-5. J Nat Prod 74(10): 2219–2223. doi:10.1021/np200597m Fu P, Wang SX, Hong K, Li X, Liu PP, Wang Y, Zhu WM (2011b) Cytotoxic bipyridines from the marine-derived actinomycete Actinoalloteichus cyanogriseus WH1-2216-6. J Nat Prod 74(8): 1751–1756. doi:10.1021/Np200258h Galm U, Shen B (2007) Natural product drug discovery: the times have never been better. Chem Biol 14(10):1098–1104. doi:10.1016/j. chembiol.2007.10.004 Gao SS, Li XM, Zhang Y, Li CS, Cui CM, Wang BG (2011) Comazaphilones A-F, azaphilone derivatives from the marine sediment-derived fungus Penicillium commune QSD-17. J Nat Prod 74(2):256–261. doi:10.1021/Np100788h Gastineau R, Pouvreau JB, Hellio C, Morancais M, Fleurence J, Gaudin P, Bourgougnon N, Mouget JL (2012) Biological activities of purified marennine, the blue pigment responsible for the greening of oysters. J Agric Food Chem 60(14):3599–3605. doi:10.1021/ Jf205004x Gupta P, Sharma U, Schulz TC, McLean AB, Robins AJ, West LM (2012) Bicyclic C21 terpenoids from the marine sponge Clathria compressa. J Nat Prod 75(6):1223–1227. doi:10.1021/np300265p Guzman-Murillo MA, Ascencio F (2000) Anti-adhesive activity of sulphated exopolysaccharides of microalgae on attachment of red sore disease-associated bacteria and Helicobacter pylori to tissue culture cells. Lett Appl Microbiol 30(6):473–478 Han Z, Xu Y, McConnell O, Liu LL, Li YX, Qi SH, Huang XZ, Qian PY (2012) Two antimycin A analogues from marine-derived actinomycete Streptomyces lusitanus. Mar Drugs 10(3):668–676. doi:10. 3390/Md10030668 Haste NM, Thienphrapa W, Tran DN, Loesgen S, Sun P, Nam SJ, Jensen PR, Fenical W, Sakoulas G, Nizet V, Hensler ME (2012) Activity of the thiopeptide antibiotic nosiheptide against contemporary strains of methicillin-resistant Staphylococcus aureus. J Antibiot Tokyo 65(12):593–598. doi:10.1038/Ja.2012.77 Hawas UW, El-Beih AA, El-Halawany AM (2012) Bioactive anthraquinones from endophytic fungus Aspergillus versicolor isolated from red sea algae. Arch Pharm Res 35(10):1749–1756. doi:10.1007/ s12272-012-1006-x Hayes M, Carney B, Slater J, Bruck W (2008) Mining marine shellfish wastes for bioactive molecules: chitin and chitosan–part B: applications. Biotechnol J 3(7):878–889. doi:10.1002/biot.200800027 Herbiniere J, Braquart-Varnier C, Greve P, Strub JM, Frere J, Van Dorsselaer A, Martin G (2005) Armadillidin: a novel glycine-rich antibacterial peptide directed against gram-positive bacteria in the woodlouse Armadillidium vulgare (Terrestrial Isopod, Crustacean). Dev Comp Immunol 29(6):489–499. doi:10.1016/j.dci.2004.11.001 Hossain GS, Li J, Shin HD, Du G, Liu L, Chen J (2014) L-Amino acid oxidases from microbial sources: types, properties, functions, and applications. Appl Microbiol Biotechnol 98(4):1507–1515. doi:10. 1007/s00253-013-5444-2 Huang LS, He F, Huang H, Zhang XY, Qi SH (2012) Carbamate derivatives and sesquiterpenoids from the South China Sea gorgonian Melitodes squamata. Beilstein J Org Chem 8:170–176. doi:10. 3762/Bjoc.8.18 Huang HN, Rajanbabu V, Pan CY, Chan YL, Wu CJ, Chen JY (2013) Use of the antimicrobial peptide Epinecidin-1 to protect against MRSA infection in mice with skin injuries. Biomaterials 34(38):10319– 10327. doi:10.1016/j.biomaterials.2013.09.037

Appl Microbiol Biotechnol Ibrahim SRM, Min CC, Teuscher F, Ebel R, Kakoschke C, Lin WH, Wray V, Edrada-Ebel R, Proksch P (2010) Callyaerins A-F and H, new cytotoxic cyclic peptides from the Indonesian marine sponge Callyspongia aerizusa. Bioorg Med Chem 18(14):4947–4956. doi: 10.1016/j.bmc.2010.06.012 Ines T, Amina B, Khaled S, Kamel G (2007) Screening of antimicrobial activity of marine sponge extracts collected from Tunisian coast. Proc West Pharmacol Soc 50:152–155 Isnansetyo A, Kamei Y (2009) Anti-methicillin-resistant Staphylococcus aureus (MRSA) activity of MC21-B, an antibacterial compound produced by the marine bacterium Pseudoalteromonas phenolica O-BC30T. Int J Antimicrob Agents 34(2):131–135. doi:10.1016/j. ijantimicag.2009.02.009 Jarmila V, Vavrikova E (2011) Chitosan derivatives with antimicrobial, antitumour and antioxidant activities-a review. Curr Pharm Des 17(32):3596–3607 Jiao WC, Zhang FH, Zhao XQ, Hu JH, Suh JW (2013) A novel alkaloid from marine-derived actinomycete Streptomyces xinghaiensis with broad-spectrum antibacterial and cytotoxic activities. Plos One 8(10) doi:ARTN e75994DOI 10.1371/journal.pone.0075994 Kalinovskaya NI, Kalinovsky AI, Romanenko LA, Dmitrenok PS, Kuznetsova TA (2010) New angucyclines and antimicrobial diketopiperazines from the marine mollusk-derived actinomycete Saccharothrix espanaensis An 113. Nat Prod Commun 5(4):597– 602 Kanagasabapathy S, Samuthirapandian R, Kumaresan M (2011) Preliminary studies for a new antibiotic from the marine mollusk Melo melo (Lightfoot, 1786). Asian Pac J Trop Med 4(4):310–314. doi:10.1016/S1995-7645(11)60092-8 Kang HK, Seo CH, Park Y (2015) Marine peptides and their antiinfective activities. Mar Drugs 13(1):618–654. doi:10.3390/ md13010618 Kasthuri SR, Wan Q, Umasuthan N, Bathige SDNK, Lim BS, Jung HB, Lee J, Whang I (2013) Genomic characterization, expression analysis, and antimicrobial function of a glyrichin homologue from rock bream, Oplegnathus fasciatus. Fish Shellfish Immunol 35(5):1406– 1415. doi:10.1016/j.fsi.2013.08.008 Kavita K, Singh VK, Jha B (2013) 24-Branched Delta5 sterols from Laurencia papillosa red seaweed with antibacterial activity against human pathogenic bacteria. Microbiol Res 169(4):301–306. doi:10. 1016/j.micres.2013.07.002 Kawanishi T, Shiraishi T, Okano Y, Sugawara K, Hashimoto M, Maejima K, Komatsu K, Kakizawa S, Yamaji Y, Hamamoto H, Oshima K, Namba S (2011) New detection systems of bacteria using highly selective media designed by SMART: selective medium-design algorithm restricted by two constraints. PLoS ONE 6(1):e16512. doi: 10.1371/journal.pone.0016512 Khamthong N, Rukachaisirikul V, Tadpetch K, Kaewpet M, Phongpaichit S, Preedanon S, Sakayaroj J (2012) Tetrahydroanthraquinone and xanthone derivatives from the marine-derived fungus Trichoderma aureoviride PSU-F95. Arch Pharm Res 35(3):461–468. doi:10. 1007/s12272-012-0309-2 Kijjoa A, Sawangwong P (2004) Drugs and cosmetics from the Sea. Mar Drugs 2(2):73–82 Kim H, Elvitigala DAS, Lee Y, Lee S, Whang I, Lee J (2012) Ferritin Hlike subunit from Manila clam (Ruditapes philippinarum): molecular insights as a potent player in host antibacterial defense. Fish Shellfish Immunol 33(4):926–936. doi:10.1016/j.fsi.2012.08.007 Kitani Y, Toyooka K, Endo M, Ishizaki S, Nagashima Y (2013) Intratissue localization of an antibacterial L-amino acid oxidase in the rockfish Sebastes schlegeli. Dev Comp Immunol 39(4):456–459. doi:10.1016/j.dci.2012.12.008 Koehn FE, Carter GT (2005) The evolving role of natural products in drug discovery. Nat Rev Drug Discov 4(3):206–220. doi:10.1038/ nrd1657

Kubota T, Kamijyo Y, Takahashi-Nakaguchi A, Fromont J, Gonoi T, Kobayashi J (2013) Zamamiphidin A, a new manzamine related alkaloid from an Okinawan marine sponge Amphimedon sp. Org Lett 15(3):610–612. doi:10.1021/Ol3034274 La MP, Li C, Li L, Sun P, Tang H, Liu BS, Gong W, Han H, Yi YH, Zhang W (2012) New bioactive sulfated alkenes from the sea cucumber Apostichopus japonicus. Chem Biodivers 9(6):1166–1171. doi:10.1002/cbdv.201100324 Lam SK, Ng TB (2011) Lectins: production and practical applications. Appl Microbiol Biotechnol 89(1):45–55. doi:10.1007/s00253-0102892-9 Laport MS, Santos OC, Muricy G (2009) Marine sponges: potential sources of new antimicrobial drugs. Curr Pharm Biotechnol 10(1): 86–105 Lee SH, Peng KC, Lee LH, Pan CY, Hour AL, Her GM, Hui CF, Chen JY (2013) Characterization of tilapia (Oreochromis niloticus) viperin expression, and inhibition of bacterial growth and modulation of immune-related gene expression by electrotransfer of viperin DNA into zebrafish muscle. Vet Immunol Immunopathol 151(3–4):217– 228. doi:10.1016/j.vetimm.2012.11.010 Leeds JA, Schmitt EK, Krastel P (2006) Recent developments in antibacterial drug discovery: microbe-derived natural products-from collection to the clinic. Expert Opin Investig Drugs 15(3):211–226. doi: 10.1517/13543784.15.3.211 Leutou AS, Yun K, Choi HD, Kang JS, Son BW (2012) New production of 5-bromotoluhydroquinone and 4-O-methyltoluhydroquinone from the marine-derived fungus Dothideomycete sp. J Microbiol Biotechnol 22(1):80–83. doi:10.4014/jmb.1108.08069 Li X, Qin L (2005) Metagenomics-based drug discovery and marine microbial diversity. Trends Biotechnol 23(11):539–543. doi:10. 1016/j.tibtech.2005.08.006 Li S, Tian X, Niu S, Zhang W, Chen Y, Zhang H, Yang X, Li W, Zhang S, J u J , Z h a n g C ( 2 0 11 ) P s e u d o n o c a r d i a n s A - C , n e w diazaanthraquinone derivatives from a deap-sea actinomycete Pseudonocardia sp. SCSIO 01299. Mar Drugs 9(8):1428–1439. doi:10.3390/md9081428marinedrugs-09-01428 Li D, Xu Y, Shao CL, Yang RY, Zheng CJ, Chen YY, Fu XM, Qian PY, She ZG, de Voogd NJ, Wang CY (2012) Antibacterial bisabolanetype sesquiterpenoids from the sponge-derived fungus Aspergillus sp. Mar Drugs 10(1):234–241. doi:10.3390/Md10010234 Li MF, Chen C, Li J, Sun L (2013) The C-reactive protein of tongue sole Cynoglossus semilaevis is an acute phase protein that interacts with bacterial pathogens and stimulates the antibacterial activity of peripheral blood leukocytes. Fish Shellfish Immunol 34(2):623–631. doi:10.1016/j.fsi.2012.12.001 Li Y, Lai YM, Lu Y, Yang YL, Chen S (2014) Analysis of the biosynthesis of antibacterial cyclic dipeptides in Nocardiopsis alba. Arch Microbiol 196(11):765–774. doi:10.1007/s00203-014-1015-x Liao Z, Wang XC, Liu HH, Fan MH, Sun JJ, Shen W (2013) Molecular characterization of a novel antimicrobial peptide from Mytilus coruscus. Fish Shellfish Immunol 34(2):610–616. doi:10.1016/j. fsi.2012.11.030 Lin MC, Hui CF, Chen JY, Wu JL (2013) Truncated antimicrobial peptides from marine organisms retain anticancer activity and antibacterial activity against multidrug-resistant Staphylococcus aureus. Peptides 44:139–148. doi:10.1016/j.peptides.2013.04.004 Lin Z, Koch M, Pond CD, Mabeza G, Seronay RA, Concepcion GP, Barrows LR, Olivera BM, Schmidt EW (2014) Structure and activity of lobophorins from a turrid mollusk-associated Streptomyces sp. J Antibiot Tokyo 67(1):121–126. doi:10.1038/ja.2013.115 Liu HP, Chen RY, Zhang QX, Wang QY, Li CR, Peng H, Cai L, Zheng CQ, Wang KJ (2012) Characterization of two isoforms of antiliopolysacchride factors (Sp-ALFs) from the mud crab Scylla paramamosain. Fish Shellfish Immunol 33(1):1–10. doi:10.1016/j. fsi.2012.03.014

Appl Microbiol Biotechnol Liu Y, Cui Z, Li X, Song C, Shi G, Wang C (2013) Molecular cloning, genomic structure and antimicrobial activity of PtALF7, a unique isoform of anti-lipopolysaccharide factor from the swimming crab Portunus trituberculatus. Fish Shellfish Immunol 34(2):652–659. doi:10.1016/j.fsi.2012.12.002 Lopez-Abarrategui C, Alba A, Lima LA, Maria-Neto S, Vasconcelos IM, Oliveira JT, Dias SC, Otero-Gonzalez AJ, Franco OL (2012) Screening of antimicrobials from Caribbean sea animals and isolation of bactericidal proteins from the littoral mollusk Cenchritis muricatus. Curr Microbiol 64(5):501–505. doi:10.1007/s00284012-0096-5 Lu Y, Wang Q, Liu Y, Shao C, Chen S, Sha Z (2014) Gene cloning and expression analysis of IRF1 in half-smooth tongue sole (Cynoglossus semilaevis). Mol Biol Rep 41(6):4093–4101. doi:10. 1007/s11033-014-3279-2 Ma Z, Wang N, Hu J, Wang S (2012) Isolation and characterization of a new iturinic lipopeptide, mojavensin A produced by a marinederived bacterium Bacillus mojavensis B0621A. J Antibiot Tokyo 65(6):317–322. doi:10.1038/ja.2012.19 Mahajan G, Thomas B, Parab R, Patel ZE, Kuldharan S, Yemparala V, Mishra PD, Ranadive P, D’Souza L, Pari K, Sivaramkrishnan H (2013) In vitro and in vivo activities of antibiotic PM181104. Antimicrob Agents Chemother 57(11):5315–5319. doi:10.1128/ AAC.01059-13 Margassery LM, Kennedy J, O’Gara F, Dobson AD, Morrissey JP (2012) Diversity and antibacterial activity of bacteria isolated from the coastal marine sponges Amphilectus fucorum and Eurypon major. Lett Appl Microbiol 55(1):2–8. doi:10.1111/j.1472-765X.2012. 03256.x Marinho PR, Simas NK, Kuster RM, Duarte RS, Fracalanzza SE, Ferreira DF, Romanos MT, Muricy G, Giambiagi-Demarval M, Laport MS (2012) Antibacterial activity and cytotoxicity analysis of halistanol trisulphate from marine sponge Petromica citrina. J Antimicrob Chemother 67(10):2396–2400. doi:10.1093/jac/dks229 Martin LP, Krasner C, Rutledge T, Ibanes ML, Fernandez-Garcia EM, Kahatt C, Gomez MS, McMeekin S (2013) Phase II study of weekly PM00104 ZALYPSIS® in patients with pretreated advanced/ metastatic endometrial or cervical cancer. Med Oncol 30(3):627. doi:10.1007/s12032-013-0627-3 Martins RF, Ramos MF, Herfindal L, Sousa JA, Skaerven K, Vasconcelos VM (2008) Antimicrobial and cytotoxic assessment of marine cyanobacteria - Synechocystis and Synechococcus. Mar Drugs 6(1):1–11 Martins A, Vieira H, Gaspar H, Santos S (2014) Marketed marine natural products in the pharmaceutical and cosmeceutical industries: tips for success. Mar Drugs 12(2):1066–1101. doi:10.3390/md12021066 McArthur KA, Mitchell SS, Tsueng G, Rheingold A, White DJ, Grodberg J, Lam KS, Potts BC (2008) Lynamicins A-E, chlorinated bisindole pyrrole antibiotics from a novel marine actinomycete. J Nat Prod 71(10):1732–1737. doi:10.1021/np800286d Miao FP, Li XD, Liu XH, Cichewicz RH, Ji NY (2012) Secondary metabolites from an algicolous Aspergillus versicolor strain. Mar Drugs 10(1):131–139. doi:10.3390/md10010131marinedrugs-10-00131 Mondol MA, Shahidullah Tareq F, Kim JH, Lee MA, Lee HS, Lee JS, Lee YJ, Shin HJ (2013) New antimicrobial compounds from a marine-derived Bacillus sp. J Antibiot Tokyo 66(2):89–95. doi:10. 1038/ja.2012.102 Montaser R, Abboud KA, Paul VJ, Luesch H (2011) Pitiprolamide, a proline-rich dolastatin 16 analogue from the marine cyanobacterium Lyngbya majuscula from Guam. J Nat Prod 74(1):109–112. doi:10. 1021/np1006839 Nathan C (2004) Antibiotics at the crossroads. Nature 431(7011):899– 902. doi:10.1038/431899a Newman DJ, Cragg GM (2012) Natural products as sources of new drugs over the 30 years from 1981 to 2010. J Nat Prod 75(3):311–335. doi: 10.1021/np200906s

Ng TB, Cheung RCF, Wong JH, Ye XJ (2013) Antimicrobial activity of defensins and defensin-like peptides with special emphasis on those from fungi and invertebrate animals. Curr Protein Pept Sci 14(6): 515–531 Ngai PH, Ng TB (2004) A napin-like polypeptide with translation-inhibitory, trypsin-inhibitory, antiproliferative and antibacterial activities from kale seeds. J Pept Res 64(5):202–208. doi:10.1111/j.13993011.2004.00186.x Ngai PH, Ng TB (2007) A mannose-specific tetrameric lectin with mitogenic and antibacterial activities from the ovary of a teleost, the cobia (Rachycentron canadum). Appl Microbiol Biotechnol 74(2): 433–438. doi:10.1007/s00253-006-0649-2 Pan CY, Chen JY, Cheng YS, Chen CY, Ni IH, Sheen JF, Pan YL, Kuo CM (2007) Gene expression and localization of the epinecidin-1 antimicrobial peptide in the grouper (Epinephelus coioides), and its role in protecting fish against pathogenic infection. DNA Cell Biol 26(6):403–413. doi:10.1089/dna.2006.0564 Pan CY, Wu JL, Hui CF, Lin CH, Chen JY (2011) Insights into the antibacterial and immunomodulatory functions of the antimicrobial peptide, epinecidin-1, against Vibrio vulnificus infection in zebrafish. Fish Shellfish Immunol 31(6):1019–1025. doi:10.1016/ j.fsi.2011.09.001 Penesyan A, Kjelleberg S, Egan S (2010) Development of novel drugs from marine surface associated microorganisms. Mar Drugs 8(3): 438–459. doi:10.3390/md8030438 Peng H, Liu HP, Chen B, Hao H, Wang KJ (2012) Optimized production of scygonadin in Pichia pastoris and analysis of its antimicrobial and antiviral activities. Protein Expr Purif 82(1):37–44. doi:10.1016/ j.pep.2011.11.008 Piel J (2009) Metabolites from symbiotic bacteria. Nat Prod Rep 26(3): 338–362. doi:10.1039/b703499g Porto WF, Fensterseifer GM, Franco OL (2014) In silico identification, structural characterization, and phylogenetic analysis of MdesDEF2: a novel defensin from the Hessian fly, Mayetiola destructor. J Mol Model 20(7):2339. doi:10.1007/s00894-014-2339-9 Pruksakorn P, Arai M, Kotoku N, Vilcheze C, Baughn AD, Moodley P, Jacobs WR Jr, Kobayashi M (2010) Trichoderins, novel aminolipopeptides from a marine sponge-derived Trichoderma sp., are active against dormant mycobacteria. Bioorg Med Chem Lett 20(12):3658–3663. doi:10.1016/j.bmcl.2010.04.100 Pruksakorn P, Arai M, Liu L, Moodley P, Jacobs WR Jr, Kobayashi M (2011) Action-mechanism of trichoderin A, an anti-dormant mycobacterial aminolipopeptide from marine sponge-derived Trichoderma sp. Biol Pharm Bull 34(8):1287–1290 Qi J, Shao CL, Li ZY, Gan LS, Fu XM, Bian WT, Zhao HY, Wang CY (2013) Isocoumarin derivatives and benzofurans from a spongederived Penicillium sp. fungus. J Nat Prod 76(4):571–579. doi:10. 1021/np3007556 Qin Z, Huang S, Yu Y, Deng H (2013) Dithiolopyrrolone natural products: isolation, synthesis and biosynthesis. Mar Drugs 11(10):3970– 3997. doi:10.3390/md11103970 Qu H, Chen B, Peng H, Wang K (2013) Molecular cloning, recombinant expression, and antimicrobial activity of EC-hepcidin3, a new fourcysteine hepcidin isoform from Epinephelus coioides. Biosci Biotechnol Biochem 77(1):103–110. doi:10.1271/bbb.120600 Rice LB (2006) Antimicrobial resistance in gram-positive bacteria. Am J Infect Control 34(5 Suppl 1):S11–S19. doi:10.1016/j.ajic.2006.05. 220, discussion S64-73 Sarika AR, Lipton AP, Aishwarya MS, Dhivya RS (2012) Isolation of a bacteriocin-producing lactococcus lactis and application of its bacteriocin to manage spoilage bacteria in high-value marine fish under different storage temperatures. Appl Biochem Biotechnol 167(5): 1280–1289. doi:10.1007/s12010-012-9701-0 Schulz D, Ohlendorf B, Zinecker H, Schmaljohann R, Imhoff JF (2011) Eutypoids B-E produced by a Penicillium sp. strain from the North Sea. J Nat Prod 74(1):99–101. doi:10.1021/np100633k

Appl Microbiol Biotechnol Shnit-Orland M, Sivan A, Kushmaro A (2012) Antibacterial activity of Pseudoalteromonas in the coral holobiont. Microb Ecol 64(4):851– 859. doi:10.1007/s00248-012-0086-y Silber J, Ohlendorf B, Labes A, Erhard A, Imhoff JF (2013) Calcarides AE, antibacterial macrocyclic and linear polyesters from a Calcarisporium strain. Mar Drugs 11(9):3309–3323. doi:10.3390/ md11093309 Sivasubramanian K, Ravichandran S, Kumaresan M (2011) Preliminary studies for a new antibiotic from the marine mollusk Melo melo (Lightfoot, 1786). Asian Pac J Trop Med 4(4):310–314. doi:10. 1016/S1995-7645(11)60092-8 Song Y, Huang H, Chen Y, Ding J, Zhang Y, Sun A, Zhang W, Ju J (2013) Cytotoxic and antibacterial marfuraquinocins from the deep South China Sea-derived Streptomyces niveus SCSIO 3406. J Nat Prod 76(12):2263–2268. doi:10.1021/np4006025 Souza AL, Diaz-Dellavalle P, Cabrera A, Larranaga P, Dalla-Rizza M, De-Simone SG (2013) Antimicrobial activity of pleurocidin is retained in Plc-2, a C-terminal 12-amino acid fragment. Peptides 45:78–84. doi:10.1016/j.peptides.2013.03.030 Subramanian B, Sangappellai T, Rajak RC, Diraviam B (2011) Pharmacological and biomedical properties of sea anemones Paracondactylis indicus, Paracondactylis sinensis, Heteractis magnifica and Stichodactyla haddoni from East coast of India. Asian Pac J Trop Med 4(9):722–726. doi:10.1016/S1995-7645(11) 60181-8 Sunga MJ, Teisan S, Tsueng G, Macherla VR, Lam KS (2008) Seawater requirement for the production of lipoxazolidinones by marine actinomycete strain NPS8920. J Ind Microbiol Biotechnol 35(7):761– 765. doi:10.1007/s10295-008-0344-7 Tareq FS, Lee MA, Lee HS, Lee JS, Lee YJ, Shin HJ (2014) Gageostatins A-C, antimicrobial linear lipopeptides from a marine Bacillus subtilis. Mar Drugs 12(2):871–885. doi:10.3390/md12020871 Troskie AM, Rautenbach M, Delattin N, Vosloo JA, Dathe M, Cammue BP, Thevissen K (2014) Synergistic activity of the tyrocidines, antimicrobial cyclodecapeptides from Bacillus aneurinolyticus, with amphotericin B and caspofungin against Candida albicans biofilms. Antimicrob Agents Chemother 58(7):3697–3707. doi:10.1128/ AAC.02381-14 Trujillo JI, Meyers MJ, Anderson DR, Hegde S, Mahoney MW, Vernier WF, Buchler IP, Wu KK, Yang S, Hartmann SJ, Reitz DB (2007) Novel tetrahydro-beta-carboline-1-carboxylic acids as inhibitors of mitogen activated protein kinase-activated protein kinase 2 (MK-2). Bioorg Med Chem Lett 17(16):4657–4663. doi:10.1016/j.bmcl. 2007.05.070 Tsoukalas N, Tolia M, Lypas G, Panopoulos C, Barbounis V, Koumakis G, Efremidis A (2014) Complete remission of a reccurrent mesenteric liposarcoma with rare histological features following the administration of trabectedin. Oncol Lett 7(1):47–49. doi:10.3892/ol. 2013.1646ol-07-01-0047 Valliappan K, Sun W, Li Z (2014) Marine actinobacteria associated with marine organisms and their potentials in producing pharmaceutical natural products. Appl Microbiol Biotechnol 98(17):7365–7377. doi:10.1007/s00253-014-5954-6 Vo TS, Kim SK, Se-Kwon K (2014) Chapter one—marine-derived polysaccharides for regulation of allergic responses. Adv Food Nutr Res 73 Academic Press 1–13 von Nussbaum F, Brands M, Hinzen B, Weigand S, Habich D (2006) Antibacterial natural products in medicinal chemistry-exodus or revival? Angew Chem Int Ed Engl 45(31):5072–5129. doi:10.1002/ anie.200600350 von Schwarzenberg K, Vollmar AM (2013) Targeting apoptosis pathways by natural compounds in cancer: marine compounds as lead structures and chemical tools for cancer therapy. Cancer Lett 332(2):295– 303. doi:10.1016/j.canlet.2010.07.004 Wagner-Dobler I, Beil W, Lang S, Meiners M, Laatsch H (2002) Integrated approach to explore the potential of marine

microorganisms for the production of bioactive metabolites. Adv Biochem Eng Biotechnol 74:207–238 Wang R, Liu TM, Shen MH, Yang MQ, Feng QY, Tang XM, Li XM (2012) Spiculisporic acids B-D, three new gamma-butenolide derivatives from a sea urchin-derived fungus Aspergillus sp. HDf2. Molecules 17(11):13175–13182. doi:10.3390/molecules171113175 Wang ML, Lu CH, Xu QY, Song SY, Hu ZY, Zheng ZH (2013a) Four new citrinin derivatives from a marine-derived Penicillium sp. fungal strain. Molecules 18(5):5723–5735. doi:10.3390/ molecules18055723 Wang Z, Fu P, Liu P, Wang P, Hou J, Li W, Zhu W (2013b) New pyran-2ones from alkalophilic actinomycete, Nocardiopsis alkaliphila sp. Nov. YIM-80379. Chem Biodivers 10(2):281–287. doi:10.1002/ cbdv.201200086 Waters AL, Hill RT, Place AR, Hamann MT (2010) The expanding role of marine microbes in pharmaceutical development. Curr Opin Biotechnol 21(6):780–786. doi:10.1016/j.copbio.2010.09.013 Wilmes M, Cammue BP, Sahl HG, Thevissen K (2011) Antibiotic activities of host defense peptides: more to it than lipid bilayer perturbation. Nat Prod Rep 28(8):1350–1358. doi:10.1039/c1np00022e Wong JH, Zhang XQ, Wang HX, Ng TB (2006) A mitogenic defensin from white cloud beans (Phaseolus vulgaris). Peptides 27(9):2075– 2081. doi:10.1016/j.peptides.2006.03.020 Wong JH, Legowska A, Rolka K, Ng TB, Hui M, Cho CH, Lam WW, Au SW, Gu OW, Wan DC (2011a) Effects of cathelicidin and its fragments on three key enzymes of HIV-1. Peptides 32(6):1117–1122. doi:10.1016/j.peptides.2011.04.017 Wong JH, Ng TB, Legowska A, Rolka K, Hui M, Cho CH (2011b) Antifungal action of human cathelicidin fragment (LL13-37) on Candida albicans. Peptides 32(10):1996–2002. doi:10.1016/j. peptides.2011.08.018 Wong JH, Ye XJ, Ng TB (2013) Cathelicidins: peptides with antimicrobial, immunomodulatory, anti-inflammatory, angiogenic, anticancer and procancer activities. Curr Protein Pept Sci 14(6):504–514 Woodford N (2005) Biological counterstrike: antibiotic resistance mechanisms of Gram-positive cocci. Clin Microbiol Infect 11(3):2–21. doi:10.1111/j.1469-0691.2005.01140.x Wu Z, Li S, Li J, Chen Y, Saurav K, Zhang Q, Zhang H, Zhang W, Zhang S, Z h a ng C ( 20 1 3 ) A n t i b a c te r i a l an d c yt o t o x i c n e w napyradiomycins from the marine-derived Streptomyces sp. SCSIO 10428. Mar Drugs 11(6):2113–2125. doi:10.3390/ md11062113 Wu B, Liu Z, Zhou L, Ji G, Yang A (2015) Molecular cloning, expression, purification and characterization of vitellogenin in scallop Patinopecten yessoensis with special emphasis on its antibacterial activity. Dev Comp Immunol 49(2):249–258 Wyche TP, Hou Y, Vazquez-Rivera E, Braun D, Bugni TS (2012) Peptidolipins B-F, antibacterial lipopeptides from an ascidianderived Nocardia sp. J Nat Prod 75(4):735–740. doi:10.1021/ np300016r Xin W, Ye X, Yu S, Lian XY, Zhang Z (2012) New capoamycin-type antibiotics and polyene acids from marine Streptomyces fradiae PTZ0025. Mar Drugs 10(11):2388–2402. doi:10.3390/ md10112388 Xu M, Davis RA, Feng Y, Sykes ML, Shelper T, Avery VM, Camp D, Quinn RJ (2012) Ianthelliformisamines A-C, antibacterial bromotyrosine-derived metabolites from the marine sponge Suberea ianthelliformis. J Nat Prod 75(5):1001–1005. doi:10. 1021/np300147d Yang L, Fan M, Liu X, Wu M, Shi G, Liao Z (2011) Solution structure and antibacterial mechanism of two synthetic antimicrobial peptides. Sheng Wu Gong Cheng Xue Bao 27(11):1564–1573 Yang F, Hamann MT, Zou Y, Zhang MY, Gong XB, Xiao JR, Chen WS, Lin HW (2012) Antimicrobial metabolites from the Paracel Islands sponge Agelas mauritiana. J Nat Prod 75(4):774–778. doi:10.1021/ np2009016

Appl Microbiol Biotechnol Yau T, Dan X, Ng CC, Ng TB (2015) Lectins with potential for anticancer therapy. Molecules 20(3):3791–3810. doi:10.3390/ molecules20033791 Ye XJ, Ng TB, Wu ZJ, Xie LH, Fang EF, Wong JH, Pan WL, Wing SS, Zhang YB (2011) Protein from red cabbage (Brassica oleracea) seeds with antifungal, antibacterial, and anticancer activities. J Agric Food Chem 59(18):10232–10238. doi:10.1021/jf201874j Yin C, Wong JH, Ng TB (2014) Recent studies on the antimicrobial peptides lactoferricin and lactoferrampin. Curr Mol Med 14(9): 1139–1154 Yu LP, Sun BG, Li J, Sun L (2013) Characterization of a c-type lysozyme of Scophthalmus maximus: expression, activity, and antibacterial effect. Fish Shellfish Immunol 34(1):46–54. doi:10.1016/j.fsi. 2012.10.007 Zarai Z, Gharsallah H, Hammami A, Mejdoub H, Bezzine S, Gargouri YT (2012) Antibacterial, anti-chlamydial, and cytotoxic activities of a marine snail (Hexaplex trunculus) phospholipase A2: an in vitro study. Appl Biochem Biotechnol 168(4):877–886. doi:10.1007/ s12010-012-9826-1 Zhang S, Sun Y, Pang Q, Shi X (2005) Hemagglutinating and antibacterial activities of vitellogenin. Fish Shellfish Immunol 19(1):93–95. doi:10.1016/j.fsi.2004.10.008 Zhang S, Wang S, Li H, Li L (2011) Vitellogenin, a multivalent sensor and an antimicrobial effector. Int J Biochem Cell Biol 43(3):303– 305. doi:10.1016/j.biocel.2010.11.003 Zhang L, Li DL, Chen YC, Tao MH, Zhang WM (2012a) Study on secondary metabolites of marine fungus Penicillium sp. FS60 from the South China Sea. Zhong Yao Cai 35(7):1091–1094 Zhang XY, Bao J, Wang GH, He F, Xu XY, Qi SH (2012b) Diversity and antimicrobial activity of culturable fungi isolated from six species of

the South China Sea gorgonians. Microb Ecol 64(3):617–627. doi: 10.1007/s00248-012-0050-x Zhang J, Yu LP, Li MF, Sun L (2014a) Turbot (Scophthalmus maximus) hepcidin-1 and hepcidin-2 possess antimicrobial activity and promote resistance against bacterial and viral infection. Fish Shellfish Immunol 38(1):127–134. doi:10.1016/j.fsi.2014.03.011 Zhang M, Li MF, Sun L (2014b) NKLP27: a teleost NK-lysin peptide that modulates immune response, induces degradation of bacterial DNA, and inhibits bacterial and viral infection. PLoS ONE 9(9):e106543. doi:10.1371/journal.pone.0106543PONE-D-14-18969 Zhao HY, Shao CL, Li ZY, Han L, Cao F, Wang CY (2013) Bioactive pregnane steroids from a South China Sea gorgonian Carijoa sp. Molecules 18(3):3458–3466. doi:10.3390/molecules18033458 Zheng S, Liu Q, Zhang G, Wang H, Ng TB (2010) Purification and characterization of an antibacterial protein from dried fruiting bodies of the wild mushroom Clitocybe sinopica. Acta Biochim Pol 57(1): 43–48 Zheng J, Wang Y, Wang J, Liu P, Li J, Zhu W (2013) Antimicrobial ergosteroids and pyrrole derivatives from halotolerant Aspergillus flocculosus PT05-1 cultured in a hypersaline medium. Extremophiles 17(6):963–971. doi:10.1007/s00792-013-0578-9 Zhou X, Huang H, Chen Y, Tan J, Song Y, Zou J, Tian X, Hua Y, Ju J (2012a) Marthiapeptide A, an anti-infective and cytotoxic polythiazole cyclopeptide from a 60 L scale fermentation of the deep sea-derived Marinactinospora thermotolerans SCSIO 00652. J Nat Prod 75(12):2251–2255. doi:10.1021/np300554f Zhou Z, Ni D, Wang M, Wang L, Shi X, Yue F, Liu R, Song L (2012b) The phenoloxidase activity and antibacterial function of a tyrosinase from scallop Chlamys farreri. Fish Shellfish Immunol 33(2):375– 381. doi:10.1016/j.fsi.2012.05.022

Antibacterial products of marine organisms.

Marine organisms comprising microbes, plants, invertebrates, and vertebrates elaborate an impressive array of structurally diverse antimicrobial produ...
1MB Sizes 1 Downloads 11 Views