Combating Antimicrobial Resistance in Foodborne Microorganisms.

321 Journal of Food Protection, Vol. 79, No. 2, 2016, Pages 321–336 doi:10.4315/0362-028X.JFP-15-023 Copyright Q, International Association for Food Protection

Review

Combating Antimicrobial Resistance in Foodborne Microorganisms EDWARD P. C. LAI,* ZAFAR IQBAL,

AND

TYLER J. AVIS

Department of Chemistry, Carleton University, 1125 Colonel By Drive, Ottawa, Ontario, Canada K1S 5B6 MS 15-023: Received 20 January 2015/Accepted 13 October 2015

ABSTRACT This review addresses an important public health hazard affecting food safety. Antimicrobial agents are used in foods to reduce or eliminate microorganisms that cause disease. Many traditional organic compounds, novel synthetic organic agents, natural products, peptides, and proteins have been extensively studied for their effectiveness as antimicrobial agents against foodborne Campylobacter spp., Escherichia coli, Listeria spp. and Salmonella. However, antimicrobial resistance can develop in microorganisms, enhancing their ability to withstand the inhibiting or killing action of antimicrobial agents. Knowledge gaps still exist with regard to the actual chemical and microbiological mechanisms that must be identified to facilitate the search for new antimicrobial agents. Technical implementation of antimicrobial active packing films and coatings against target microorganisms must also be improved for extended product shelf life. Recent advances in antimicrobial susceptibility testing can provide researchers with new momentum to pursue their quest for a resistance panacea. Key words: Active packaging: Antimicrobial resistance: Chemical mechanisms: Natural products: Synthetic agents

PUBLIC HEALTH SIGNIFICANCE OF ANTIMICROBIAL-RESISTANT BACTERIA Foodborne pathogenic microorganisms present a direct risk to public health (20, 121). Globally, 2.2 million people die every year from diarrhea caused by contaminated food and water, including 700,000 diarrheal deaths among children in Southeast Asia (122). In agriculture, antimicrobial agents are used to treat, control, or prevent diseases caused by microorganisms, but use of these agents can select for antimicrobial-resistant bacteria (123). Resistance genes may also be introduced during food processing through the use of starter cultures, probiotics, bacteriophages, etc. (113). Cross-contamination can also introduce antimicrobial-resistant bacteria into the food system at any time during processing or storage (123). Although processes that destroy bacteria in food would decrease the risk of transmission of antimicrobial resistance, minimally processes foods may increase the presence of resistant bacteria and the potential for resistance transfer (113). The transmission dynamics for multidrug-resistant (MDR) agents through the food chain for foods not receiving lethality treatments (e.g., fruits, vegetables, and mollusks intended for raw consumption) is also significant. Raw fruits and vegetables, irrespective of their mode of production, can be heavily contaminated with gram-negative bacteria (94). Most of these bacteria, which originated in the soil and environment, were resistant to multiple antibiotics, including third-generation cephalospo* Author for correspondence. Tel: 613-520-2600, Ext 3835; Fax: 613-520-3749; E-mail: [email protected].

rins. Thus, both organic and conventional fruits and vegetables may constitute significant sources of resistant bacteria and of antimicrobial resistance genes. The potential impact of these bacteria on human health should never be underestimated. In the particular case of antimicrobial agents used in agricultural production, their misuse or overuse may produce antimicrobial-resistant bacteria (113). Currently, 80% of all antibiotics sold in the United States are given to poultry and livestock (80). Resistance genes can be transferred from agricultural and food bacteria, via gene swapping, to bacteria that cause diseases in people. This issue is a worldwide public health concern because a resistant infection can spread from one person to many others (90). The Preservation of Antibiotics for Medical Treatment Act was reintroduced in the United States to regulate the use of eight critical classes of antibiotics; these should not be routinely fed to healthy animals for disease prevention or growth promotion and should be reserved for sick animals (132). A pan-Canadian antimicrobial resistance strategy was recommended that would include periodic review of all medicinal antimicrobials to determine whether their approved uses and availability in veterinary medicine increased the risk that these antimicrobials would become ineffective for treating infections in humans (82). Surveillance systems, like those stewarded by the Public Health Agency of Canada, provide timely collection and analysis of reliable data on antimicrobial use and resistance (47). Scientists examine the factors that may lead to the presence of antimicrobial-resistant bacteria in food and animals to provide appropriate risk assessment to decision makers (37).

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FIGURE 1. Overview of current research activities and potential technical applications of antimicrobial agents.

At a White House forum on antibiotic stewardship, food companies and animal health stakeholders committed to implementing changes over the next 5 years to slow the emergence of resistant bacteria and prevent the spread of resistant infections (83). McDonald’s Corporation (74) has outlined four guiding principles for judicious use of antimicrobials on all farm operations raising food animals, prohibiting the use in food animals of antimicrobials that are by World Health Organization definition critically important to human medicine. This review focuses on the literature recently published in the field of antimicrobial resistance. Many scientific articles concerning novel antimicrobial agents have been collected to compare these agents with traditional organic compounds with regard to drug-resistant bacteria. Novel synthetic organic agents, natural products, peptides, proteins, and polymeric materials have been extensively tested for their effectiveness as antimicrobial agents. The use of novel antimicrobial agents is greatly needed whenever antimicrobial resistance threatens to compromise the treatment of bacterial infectious diseases (44). Here, we describe their current effectiveness and then comment on the technical implementation of these intervention products (Fig. 1). Because microorganisms can develop resistance against the novel antimicrobial agents, concerted efforts will continuously be needed to test more novel antimicrobial agents that can help the agriculture and food industries mitigate the antimicrobial resistance problem.

ANTIMICROBIAL RESISTANCE Campylobacter, Salmonella, Escherichia coli, and Listeria are among the most significant zoonotic pathogens causing foodborne diseases (79). Campylobacter jejuni is a leading cause of foodborne gastrointestinal illnesses worldwide and is increasingly resistant to clinically important antibiotics (28). Mutator strains play an important role in the emergence of antibiotic-resistant bacteria. The G595T mutation in mutY abolishes its antimutator function and

confers a mutator phenotype in Campylobacter, promoting the emergence of antibiotic-resistant Campylobacter. In a study conducted to determine the epidemiology and antimicrobial resistance of Campylobacter in human stool specimens (58), the majority (84.6%) of the isolates were C. jejuni. Isolates had the highest resistance (95.6%) to colistin sulfate and the lowest resistance to ciprofloxacin (22.1%). The rates of resistance for other antibiotics (azithromycin, erythromycin, tetracycline, cephalothin, gentamicin, nalidixic acid, ampicillin, amoxicillin, norfloxacin, and chloramphenicol) were 44.1 to 89%. Human illness was associated with young age and consumption of chicken meat and prepared salad. Pigs can be infected with Campylobacter, and fecal contamination of meat during slaughter is a food safety risk (2). A positive correlation was found between Campylobacter levels in fecal, rectal contents, and rib meat samples. Campylobacter and Salmonella isolates from humans and animals have significant rates of resistance to common antimicrobial agents (38). The confirmed fecal contamination of rib meat can transmit pathogenic bacteria to consumers when the meat is undercooked, causing foodborne disease. Meat products are a demonstrable source of antibioticresistant Salmonella strains, which is a serious concern for food safety. In one study, 106 Salmonella strains were isolated from poultry, pork, and beef in Poland (70). The three most common Salmonella serotypes identified were Enteritidis, Infantis, and Typhimurium. When subjected to antimicrobial susceptibility testing, 69% of the Salmonella strains were resistant to one or more families of antibiotics. Salmonella strains isolated from poultry meat had the widest spectrum of resistance. The most common resistance observed among these Salmonella isolates was to nalidixic acid. Many of these isolates also were resistant to tetracycline, ampicillin, streptomycin, and sulfonamides. However, all tested strains were susceptible to cefepime, cefotaxime, ceftazidime, ceftriaxone, ciprofloxacin, ertapenem, and imipenem. In a study of the antimicrobial


COMBATING RESISTANCE IN FOODBORNE MICROORGANISMS

resistance patterns of 19 Salmonella isolates recovered from the feces and tissues of farm animals with salmonellosis (48), 18 isolates were resistant to oxytetracycline, and 5 were resistant to more than one type of drug. The majority of Salmonella Typhi isolates from Bangladesh and Vietnam were multidrug resistant and belonged to the widespread haplotype H58 clone (24). Several resistance mechanisms, including alterations in gyrase A, the presence of qnrS, and enhanced efflux pumps were involved. A Salmonella genomic island was found in 18 of 26 MDR Salmonella Typhi isolates from Bangladesh. This island carried seven resistance genes that conferred resistance to five first-line antimicrobial agents. A total of 634 persons infected with seven outbreak strains of Salmonella Heidelberg were reported from 29 U.S. states and Puerto Rico from 1 March 2013 to 11 July 2014 (21). This multistate outbreak of MDR Salmonella Heidelberg infections, linked to Foster Farms brand chicken, now appears to be over. However, Salmonella remains an important cause of human illness in the United States. The U.S. Food and Drug Administration (110) recently announced the Veterinary Feed Directive, which brings the use of antimicrobial drugs under veterinary supervision so that these drugs are used only when necessary for assuring animal health. As food animal production practices in middle-income countries shift toward large-scale intensive farming operations, routine use of antimicrobial agents in subtherapeutic doses will significantly increase the global burden of antimicrobial resistance (111). The multidrug resistance of b-lactamase–producing E. coli poses real challenges to food scientists (11). Extendedspectrum b-lactamases are plasmid-encoded enzymes that inactivate a large number of b-lactam antibiotics, including extended-spectrum and very broad–spectrum cephalosporins and monobactams. These enzymes are also commonly inhibited by b-lactamase inhibitors, such as clavulanic acid, sulbactam, and tazobactam (99). Gram-negative bacteria selected from organic foods were screened for multidrug efflux pumps and specific antibiotic resistance genes (40). The acrB pump gene of the AcrAB-TolC system was detected in all isolates, but genes qacE and qacJ encoding resistance to quaternary ammonium compounds were detected only in Enterobacter isolates. The antibiotic resistance determinant most frequently found was the lsa gene. These results suggest that the main mechanisms of antibiotic resistance in gram-negative bacteria from organic foods rely on different kinds of efflux pumps of broad substrate specificity. The indiscriminate use of biocides in the food chain should be revised to minimize the persistence of antimicrobial resistance in zoonotic bacteria. Antibiotic resistance also has been reported in Listeria monocytogenes. In a study of the susceptibility of L. monocytogenes isolates from raw beef, chicken, and vegetarian patties to 11 antibiotics (120), 19 of 41 isolates were resistant to at least two antibiotics. The most common resistance was to tetracycline followed by resistance to erythromycin. However, none of the isolates were resistant to imipenem or gentamicin. In another study, raw cow, sheep, and goat milk samples collected from farm bulk tanks were positive for L. monocytogenes (54). The Listeria spp. isolates were resistant to tetracycline and penicillin G but

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susceptible to gentamicin, vancomycin, and rifampin. Multidrug resistance was also was identified in L. monocytogenes isolates from ready-to-eat meat products and meat processing environments (46). Oxacillin resistance was the most common phenotype, followed by some clindamycin resistance and low incidence of tetracycline resistance. Listeria isolates from meat products were significantly more antimicrobial resistant than Listeria isolates from the environment. The antibiotic resistance and serogroups of L. monocytogenes isolates from fish samples were compared in three developing countries (81). The isolates exhibited high resistance to penicillin, rifampin, clindamycin, erythromycin, and tetracycline but low resistance to amoxicillin– clavulanic acid, streptomycin, sulfamethoxazole-trimethoprim, gentamicin, chloramphenicol, and kanamycin.

RESEARCH NEEDS Research on combinatorial biosynthesis, including DNA-directed synthesis, is needed to find novel bioactive molecules (35). More research is needed on the chemical properties necessary for cell permeability and retention (78). Further investigation of the molecular biology underlying bacterial cell death is also needed (7), especially the genetic regulatory programs and the biochemical processes. Bacterial responses to antibiotic treatments that lead to cell death are complex, involving multiple genetic and biochemical pathways (57). The mode of action has been determined through whole-genome sequencing of resistant organisms (61). The next challenge is to improve the ability to screen multiple diverse molecules for antibiotic potential. Highdensity techniques must be developed to improve cell-based screening, moving beyond growth inhibition as the standard measure of a compound’s antimicrobial activity. These techniques include adenylate kinase release (53) and microbroth dilution assays (59) as recommended by the Clinical and Laboratory Standards Institute (formerly the U.S. National Committee for Clinical Laboratory Standards) (87).

TRADITIONAL ORGANIC ANTIMICROBIAL AGENTS In an early study, findings indicated that organic compounds could be used to kill bacteria in water and that the percentage of NH2 as a reactive functional group was the most important factor (93). Many organic compounds have been identified as antimicrobial agents, particularly amikacin, amoxicillin–clavulanic acid, cefotaxime, ceftazidime, chloramphenicol, cotrimoxazole, gentamicin, tazobactam, and tetracycline (88). The MIC is the lowest concentration of an antimicrobial agent that will inhibit the visible growth of a microorganism after overnight incubation. The relatively wide range of MICs for exemplary organic antimicrobials is shown in Table 1. A mixture of volatile organic compounds from the endophytic fungus Muscodor crispans strain B23 had antimicrobial effects against a broad range of human and plant pathogens, including fungi, bacteria, and oomycetes (62). The antimicrobial activity of nano-size benzoic and sorbic acid solubilisates was compared with that of commercial mixtures of organic acids used as meat coatings (e.g., Articoat DLP-02 and

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TABLE 1. MICs for exemplary organic antimicrobial agents Compound

Amphotericin-B Ampicillin

Azithromycin Ceftazidime Ceftriaxone

Cefuroxime Ciprofloxacin

Doxycycline Fluconazole Gentamicin Griseofulvin

Levofloxacin Miconazole

Rifampin Sulfamethoxazole-trimethoprim

Microorganism

Candida albicans Brucella melitensis Staphylococcus aureus Streptococcus pyogenes Escherichia coli Pseudomonas aeruginosa Borrelia burgdorferi B. melitensis B. burgdorferi S. aureus Bacillus subtilis E. coli P. aeruginosa B. burgdorferi S. aureus E. coli B. subtilis Salmonella Typhimurium B. burgdorferi B. melitensis C. albicans B. melitensis C. albicans Aspergillus niger Aspergillus clavatus B. melitensis C. albicans A. niger Fusarium solani Aspergillus flavus B. melitensis B. melitensis

Sulac-01, Alitecno, Quito, Ecuador) (27). The nano-size solubilisates had significantly higher antimicrobial activity than their larger equivalents. This finding opens up opportunities for the use of nano-size solubilisates derived from food compatible sources, because lower quantities are required to deliver the same antimicrobial effect. The focus of antimicrobial resistance research is finding novel antimicrobial agents to combat drug-resistant pathogens. Traditional organic antimicrobial agents lack target adaptability, and their misuse and overuse have led to the resistance epidemic among pathogenic microbes, which have an incredible ability to adapt despite their submicrometer size. Microbes inhabit literally every possible climate and environment on the planet, despite extremes of boiling or freezing temperatures, pressures sufficient to crush virtually any human-made submersible, extreme salinity, zero oxygen concentration, presence or absence of sunlight, etc. (108). The mechanism of microbial adaptability is genetic plasticity and rapid replication; many bacteria can replicate in only 20 to 30 min. More than 2 billion years ago, microbes generated both b-lactam antibiotics and blactamase enzymes to resist those antibiotics. A logical approach would be (i) to control the rate of spread of antimicrobial resistance among bacteria by not misusing or

MIC (lg/ml or mg/liter)

Reference

1.56 1.5–2.0 100–250 100–200 100–200 100–200 0.22 2.0–8.0 0.25 3.1 1.6 1.6 1.6 0.063 1.56–25 1.56–25 15–25 15–25 2 8.0–32.0 6.3 0.50–0.75 100–500

90 125 30 15

2.0–8.0 15–25

125 49

0.06–2.0 4.0–16.0 50–1,000

125 125 15

112 125 112 114

112 91 49

112 125 114 125 30 15

overusing antimicrobial agents and (ii) to find novel antimicrobial agents. These novel compounds should have such qualities as target effectiveness, rapid development, reasonable rate of return on investment, sustainable effectiveness, safety for continued use, and target adaptability.

NOVEL SYNTHETIC ORGANIC ANTIMICROBIAL AGENTS To identify new potential antimicrobial agents, 20 hybrids of marine bromopyrrole alkaloids with 1,3,4oxadiazole were designed, synthesized, and evaluated for their antibacterial and antifungal activities (91). Four of these hybrids had antibacterial activity (MIC of 1.5 lg/ml) equivalent to that of ciprofloxacin against Staphylococcus aureus and E. coli. The antifungal activity of three of the hybrids was equivalent to that of amphotericin-B. Several novel chromen-4-one derivative compounds had the same MIC of 10 lg/ml, which is up to 2.5-fold more potent than ciprofloxacin and miconazole (55). Synthetic thiazolidin-4one compounds had moderate to high activity against bacterial strains (15). Two novel N-(4-(2,6-dichloroquinolin3-yl)-6-(aryl)pyrimidin-2-yl)-2-morpholino-acetamide com-



325

TABLE 2. MICs for nonorganic (or synthetic) antimicrobial agents Compound

Amikacin Amoxicillin Bromopyrrole alkaloid oxadiazole derivatives

Manganese complexes with quinolones

Piperazine derivatives of flavone

Pyrimidine derivatives of quinoline aldehyde

Shiff bases and hydrazones of substituted pyrazoles

Thiazolidin-4-ones derivatives

Microorganism

MIC (lg/ml or mg/liter)

Reference

Borrelia burgdorferi Brucella melitensis B. burgdorferi Staphylococcus aureus Escherichia coli Candida albicans E. coli Xanthomonas campestris S. aureus Bacillus cereus Bacillus subtilis B. subtilis S. aureus E. coli Salmonella Typhimurium C. albicans Aspergillus niger Fusarium solani Aspergillus flavus E. coli Pseudomonas aeruginosa S. aureus Streptococcus pyogenes C. albicans A. niger Aspergillus clavatus S. aureus B. subtilis E. coli P. aeruginosa C. albicans S. aureus S. pyogenes E. coli P. aeruginosa C. albicans A. niger A. clavatus

256 4.0–12.0 1 1.56

112 125 112 91

2.5–50 2.5–25 2.5–25 2.5–50 2.5–50 10–95

130

pounds had considerably higher antibacterial and antifungal activity than did commercially used antibiotics (30), indicating that a combination of the hetero-aryl group on the quinoline core increased the antimicrobial activity. New 1,2,4-triazole and benzoxazole derivatives containing a substituted pyrazole moiety were synthesized, and the compound with the 2,5-dichlorothiophene substituent had significant antimicrobial activity (114). Compounds were synthesized via the three-component reactions of 5-aminopyrazoles and salicylic aldehydes with pyruvic acids, and gram-positive bacteria (Bacillus subtilis and S. aureus) were sensitive only to concentrations as high as 250 lg/ml (77). Incorporation of benzalkonium chloride and cetylpyridinium chloride enhanced the short-term antimicrobial effects of five endodontic sealers against three microorganism strains (45). Interaction of MnCl2 with enrofloxacin (Herx) and 1,10-phenanthroline (phen) formed a [Mn(erx)2(phen)] complex with pronounced antimicrobial activity against five microorganisms (130). Carbazole picrate, a new synthetic

12.5–500 25–1,000 50–500 12.5–1,000 100–1,000 25–1,000 12.5–1,000 1.6–12.5 1.6–25 3.1–25 1.6–12.5 6.3–25 50–1,000

49

30

114

5

compound, also had significant antimicrobial activity against various bacterial and fungal species (98). Table 2 presents the MICs of these synthetic antimicrobial agents for comparison with those of the organic antimicrobial agents in Table 1. Because most of these novel compounds were developed in the last 1 to 2 years, little time has been available to study their mechanism of action. Nonetheless, MDR bacteria will be less likely to be resistant to these agents than to traditional compounds.

ANTIMICROBIAL PROPERTIES OF NATURAL PRODUCTS Interest in natural antimicrobial compounds isolated from food matrices is growing. These compounds can be used in food products to control pathogenic microorganisms through various modes of action (Table 3). According to the type of matrix, different isolation and purification steps are needed (86). Acetone extracts of the lichens Evernia prunastri and Pseudoevernia furfuraceae contain physodic

Egyptian aromatic plants (Mentha piperita, Ocimum basilicum, Thymus vulgaris) Marjoram, clove, cinnamon, coriander, caraway, cumin Eucalyptus leaves, almond skins Blueberry fruit and leaf extracts

Seabuckthorn leaves

Oat bran Various plant sources Fruit nectars, honey

Cassia angustifolia (senna), Foeniculum vulgare (fennel), Pimpinella anisum (anise), Laurus nobilis (laurel), Tilia vulgaris (linden), Urtica dioica (nettle), Petroselinum crispum (parsley), Anethum graveolens (dill) Brewery waste stream

Menthol, menthone, linalool, thymol

Various phenolic compounds

Various essential oils

Phenolic compounds (chlorogenic acid, quercetin, ellagic acid, quercetin3-galactoside)

Gallic acid, rutin, quercetin-3-galactoside, quercetin-3-glucoside, myricetin, quercetin, kaempferol, isorhamnetin Various phenolic compounds

Essential oils, oleoresins

Flavonoids, phenolic acids (caffeic and ferulic acids)

Various phenolic compounds

S. aureus, E. coli, Salmonella, L. monocytogenes, E. coli O157:H7

L. monocytogenes, S. aureus, B. cereus, Salmonella, E. coli, P. aeruginosa Proteus spp., Serratia marcescens, Vibrio cholera, S. aureus, E. coli, P. aeruginosa, Stenotrophomonas maltophilia, Acinetobacter baumannii, Aeromonas schubertii, Haemophilus parahaemolyticus, Micrococcus luteus, Cellulosimicrobium cellulans, Listonella anguillarum, Helicobacter pylori, Salmonella Typhi, Mycobacterium tuberculosis B. cereus, B. subtilis, E. coli, K. pneumoniae, Morganella morganii, P. aeruginosa, S. aureus, Yersinia enterocolitica, C. albicans, Saccharomyces cerevisiae

Pathogenic bacteria (S. aureus, Salmonella Enteritidis, Enterococcus faecium, Listeria innocua, Bacillus cereus, P. aeruginosa, L. monocytogenes E. coli, Salmonella Typhi, Shigella dysenteriae, Streptococcus pneumoniae, S. aureus E. coli

Lactic acid bacteria

Bacillus mycoides, Bacillus subtilis, Escherichia coli, Klebsiella pneumoniae, Staphylococcus aureus, Aspergillus flavus, Aspergillus fumigatus, Candida albicans, Penicillium purpurescens, Penicillium verrucosum Bacteria and yeast (E. coli, Pseudomonas aeruginosa, S. aureus, Streptococcus pyogenes, C. albicans) E. coli, S. aureus, Listeria monocytogenes

Microorganisms inhibited

Interaction with or disruption of the cell membrane


Interaction with or disruption of the cell membrane Interaction with or disruption of the cell membrane Interaction with or disruption of the cell membrane


Interaction with or disruption of the cell membrane, interaction with cell wall enzymes Interaction with or disruption of the cell membrane Interaction with or disruption of the cell membrane


May affect cell wall

Reported or potential mode of action

13

4

6, 16, 72, 115, 118

103

8

129

102, 105

43

5

84

60

Reference(s)

LAI ET AL.

Phenolic compounds (e.g., protocatechuic, caffeic, p-coumaric, and ferulic acids), catechin

Acetone extracts from Evernia prunastri and Pseudoevernia furfuraceae

Source

Evernic and physodic acids

Phenolics and flavonoids

Natural products and peptides

TABLE 3. Mode of action perceived for natural products

326 J. Food Prot., Vol. 79, No. 2

103 117 Corn Celery Cultured corn sugar and vinegar Nitrates

L. monocytogenes L. monocytogenes

Various citrus fruits Cruciferous vegetables Other categories

Citric acid Isothiocyanates

S. aureus, K. pneumoniae Bacillus, Escherichia, Klebsiella, Listeria, Salmonella, Serratia, Staphylococcus

S. aureus, including a methicillin-resistant strain

Lowering of pH Plasma membrane damage, reduction of internal levels of ATP, inhibition of the activities of thioredoxin reductase and acetate kinase Lowering moisture and pH Disrupting energy metabolism

Unknown, presumably pH agent or interaction with or disruption of the cell membrane

69

86 119


Stereum hirsutum mushrooms Benzoate derivatives

Natural products and peptides

TABLE 3. Continued

Source

Microorganisms inhibited

Reported or potential mode of action

Reference(s)


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acid as the most active compound (60). Methanol extracts, infusions, and decoctions of senna, fennel, anise, laurel, linden, nettle, parsley, and dill were investigated for their antimicrobial activity against eight bacteria and two yeasts, and correlations were found between the phenolic content of each plant and the antimicrobial activity (4). Methanol extracts of the aerial parts and roots of five centaury species (Centaurium and Schenkia) all had antibacterial activity (0.05 to 0.5 mg/ml) and could be used as potent antimicrobial agents for food preservation (104). Isothiocyanates extracted from cruciferous vegetables were tested against a range of pathogenic and food spoilage bacteria, including species of Bacillus, Escherichia, Klebsiella, Listeria, Salmonella, Serratia, and Staphylococcus (119). Gram-negative bacteria were overall more sensitive to isothiocyanates than were gram-positive bacteria. The intensity of antimicrobial efficacy was highest with benzylisothiocyanate, followed by phenylethyl-isothiocyanate. Structural features such as the presence of a sulfinyl group, the size of the molecule, and the length of the hydrocarbon chain seem to be important. Essential oils extracted from Egyptian aromatic plants (Mentha piperita, Ocimum basilicum, and Thymus vulgaris) by steam distillation were tested for their inhibitory effect on bacteria and yeast (E. coli, Pseudomonas aeruginosa, S. aureus, Streptococcus pyogenes, and Candida albicans) (84). Gas chromatography revealed that the main compounds from M. piperita were menthol (35%) and menthone (20%), the main compound from O. basilicum was linalool (45%), and the main compound from T. vulgaris was thymol (75%). Sensitivity tests indicated that the most effective oil against bacteria and yeast was O. basilicum followed by T. vulgaris. O. basilicum oil was highly effective against S. pyogenes, producing a zone of inhibition more than twice the size of that produced by ampicillin. As an antifungal agent, O. basilicum oil was slightly more effective against C. albicans than was clotrimazole. The intensity of antimicrobial efficacy of the essential oils of various herbs and spices against three important food pathogens (E. coli, S. aureus, and L. monocytogenes) followed this order: marjoram . clove . cinnamon . coriander . caraway . cumin (5). The antibacterial activity of the essential oils was maintained when incorporated into alginate-clay nanocomposite films. In a study of the effects of ultrasonication and microfluidization on the antimicrobial activity of lemongrass oil– alginate nanoemulsions (96), sonication led to less effective nanoemulsions against E. coli, causing a loss of antimicrobial potential. In contrast, nanoemulsions processed by microfluidization had enhanced antimicrobial activity in proportion to the number of cycles through the microfluidization chamber. Sixty-seven essential oils, oleoresins, and pure compounds were evaluated for their antimicrobial activity against six bacterial pathogens in ready-to-eat foods (33). Allyl isothiocyanate, cinnamon Chinese cassia, cinnamon oleoresins, oregano, and red thyme had high antimicrobial activity against all tested bacteria. The growth rate of L. monocytogenes in ham was reduced by 19 and 10% when oregano and cinnamon cassia essential oils, respectively, were applied to ham at 500 ppm. Nisin, oregano essential oil, and cinnamon essential oil also were

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evaluated for their ability to inhibit the growth of L. monocytogenes on ready-to-eat ham (52). Microencapsulation of the antimicrobial formulations verified the potential effect of the polymer to maintain the antimicrobial efficiency during storage. Microencapsulated cinnamon essential oil in combination with nisin and c-irradiation (at 1.5 kGy) produced the highest bacterial radiosensitization of 5.0 compared with the control. Red wines produced in France are often treated with antimicrobial phenolic extracts (eucalyptus leaves and almond skins) containing inhibitor compounds. Molecular techniques were applied to study the evolution of wineassociated lactic acid bacteria from red wines (43). Lactic acid bacteria can antagonize pathogens by competing for nutrients and by secretion of substances with antimicrobial activity, including organic acids, peroxides, and antimicrobial polypeptides (17). Because blueberries are rich in phenolic compounds, the aqueous extracts of Vaccinium corymbosum dry fruits and leaves were evaluated for potential antimicrobial activity against several pathogenic microorganisms (105). Leaf extracts appeared to have higher antimicrobial activity than fruit extracts, but low activity was found against potentially beneficial lactic acid bacteria. The antimicrobial effect of V. corymbosum extracts on the growth of L. monocytogenes and Salmonella Enteritidis also was examined (102). L. monocytogenes was significantly more sensitive to the extracts than was Salmonella Enteritidis, and chlorogenic acid, quercetin, ellagic acid, and quercetin-3-galactoside were among the active antimicrobial phenolic compounds in the extracts. A phenolic-rich fraction was prepared from sea buckthorn (Hippophae rhamnoides) leaves by sequential fractionation (129). Gallic acid, rutin, quercetin-3-galactoside, quercetin-3-glucoside, myricetin, quercetin, kaempferol, and isorhamnetin were major constituents. The phenolic-rich fraction had a broad spectrum of growth inhibiting effects against E. coli, Salmonella Typhi, Shigella dysenteriae, Streptococcus pneumoniae, and S. aureus. Oat bran treated with carbohydrases released phenolic compounds with antimicrobial properties against E. coli, although these compounds did not adversely affect B. subtilis, a potential beneficial bacterium (8). The antimicrobial efficacy of a product containing cultured corn sugar and vinegar in cured honey ham and turkey was evaluated (103). The product controlled L. monocytogenes growth at 48C for 90 days without a negative effect on taste or shelf life. A cultured sugar–vinegar blend used on uncured turkey (117) also was effective for inhibiting the growth of L. monocytogenes, demonstrating the potential of this blend to improve food safety in uncured meats. Celery juice concentrate may increase meat pH, which could have implications for the antimicrobial impact of nitrite in some products (51). In ham, celery juice treatments resulted in growth of L. monocytogenes similar to that of the conventional nitrite at the same concentrations. Honey contains a high concentration of sugars that renders water unavailable. Its low water activity of 0.6 prevents the growth of most microorganisms, and its low pH also may explain the antimicrobial activity. Honey has a wound-healing effect due to its viscosity and the production


of hydrogen peroxide (72). Phenolic-H2O2–induced oxidative stress has been identified as the mechanism of the bacteriostatic and DNA-damaging activities of honey (16). Active honeys (MIC90 of 6 to 12%, vol/vol) have high concentrations of phenolics with high radical scavenging activity. Polyphenols extracted from honey degraded plasmid DNA in the presence of H2O2 and Cu(II) in the Fenton-type reaction. At low concentrations, honey polyphenols exerted pro-oxidant activity that was damaging to DNA. An extraction process that allows selective recovery of polyphenols from a brewery waste stream was recently developed (13). The crude extracts exhibited high antimicrobial activity against gram-positive and gram-negative bacteria. The antimicrobial activity was attributed to phenolic compounds (such as protocatechuic, caffeic, p-coumaric, and ferulic acids) and catechin. Two new benzoate derivatives isolated from the mycelia of mushrooms (69) had antimicrobial effects against S. aureus, including a methicillinresistant strain, with a MIC of 25 lg/ml. S. aureus is a common gram-positive pathogen that frequently causes chronic infection of the mammary gland in dairy cows. Farrerol, a traditional Chinese medicine isolated from rhododendron, has antibacterial activity, and the effect of farrerol on the invasion of bovine mammary epithelial cells (bMEC) by S. aureus was investigated (127). The expression of antimicrobial peptide (AMP) genes by bMEC was assessed in the presence or absence of S. aureus infection. Farrerol (4 to 16 lg/ml) reduced the internalization of S. aureus into bMEC by .55% and down-regulated the mRNA expression of tracheal AMP and bovine neutrophil b-defensin 5 in bMEC infected with S. aureus. The nitric oxide production of bMEC after S. aureus stimulation was decreased and S. aureus–induced NF-jB activation in bMEC was suppressed by farrerol treatment. These results indicate that farrerol enhanced bMEC defense against S. aureus infection and that farrerol could be useful for protection against bovine mastitis, with major economic benefits to the dairy industry. Many studies were carried out in antimicrobial-resistant bacteria, and some also involved nonresistant foodborne pathogens. Natural products may provide efficacy that is similar to or even better than that of some traditional antimicrobial treatments (51, 84). However, all antimicrobial treatments, including natural products, must be thoroughly tested to ensure that no toxicity or safety issues exist. In the food processing industry, antimicrobial agents are added to the products (e.g., poultry after slaughter) to prevent the growth of pathogenic and spoilage microorganisms. Antimicrobial agents at elevated concentrations can affect the product color, odor, taste, and texture (97). Thus, when selecting antimicrobial agents for use in food processing, the agent-induced changes in sensory aspects must be considered from the consumer’s perspective.

COMPARISON BETWEEN NOVEL SYSTEMS AND MORE TRADITIONAL ANTIMICROBIAL AGENTS Natural products with antibiotic activity (penicillins, cephalosporins, vancomycin, tetracycline and aminoglycosides) and synthetic antimicrobial agents (fluoroquinolones,



sulfonamides and oxazolidinones) have been two fruitful sources of new antibiotics (78). The field of metagenomics (which sequences the pooled genetic material of a bacterial community) has identified new natural products and novel biosynthetic pathways. Scientists have investigated ocean beds and deep caves looking for microorganisms that can make new antimicrobial compounds in the soil. This year, teixobactin produced promising results in laboratory tests against otherwise drugresistant strains of tuberculosis and against methicillinresistant S. aureus (76). If approved, teixobactin will be the first new class of antibiotics developed since 1987. Clinical trials of antibiotics are extraordinarily expensive, costing $1 billion or more, and 50 promising leads could result in the discovery of only one new drug. Researchers must develop technologies that can rapidly diagnose resistant infections, so that doctors can tailor treatments accordingly and avoid using broad-spectrum antibiotics. Unfortunately, genome technologies (19) are too expensive and cannot detect every possible resistance-associated mutation. Biotechnology companies are developing resistance breakers that punch holes in the membrane of bacteria to let antibiotics in. Can the nature of antimicrobial treatment be changed in such a way that we reduce the selection pressure on bacteria to produce antimicrobial resistance? One novel approach is to make drugs that stop bacteria from secreting virulence factor molecules that cause disease. Some drugs can interfere with the process bacteria use for communicating with each other so they do not secrete disease-causing factors. Quorum sensing controls the expression of virulence factors by pathogenic bacteria. Canonical mechanisms have been examined for inhibiting quorum sensing in pathogens with the goal of designing novel antimicrobial therapeutics (95).

AMPS AND PROTEINS AMPs and proteins are generally considered a possible solution to the multidrug resistance problem. One peptide containing an arginine-rich domain at its C-terminus offers broad-spectrum antimicrobial activity, including some MDR Acinetobacter baumannii isolates, at micromolar concentrations (23). This peptide killed gram-negative and grampositive bacteria by membrane permeabilization or DNA binding but had no detectable cytotoxicity in various tissue culture systems. In a model system in which mice were inoculated intraperitoneally with S. aureus, timely treatment with the arginine-rich peptide resulted in a 100-fold reduction of bacteria in blood, liver, and spleen and 100% protection of inoculated animals from death. A series of new iron complexes based on Schiff base ligands were synthesized from condensation of 5-bromosalicylaldehyde and a-amino acids (1). Screening against three bacteria (E. coli, P. aeruginosa, and Bacillus cereus) and three fungi (Penicillium purpurogenium, Aspergillus flavus, and Trichotheium rosium) indicated that the metal complexes had higher antibacterial and antifungal activity than the original ligands. Reactions of a new asymmetrical dicompartmental Schiff base ligand, (E)-3-(2-((E)-4-(2hydroxyphenyl)-4-oxobutan-2-ylideneamino)propylimino)indolin-2-one (H3L), with a N2O3 donor set with cobalt, copper, iron, nickel, uranyl, and vanadium salts produced a

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series of new binuclear complexes (65). The Schiff base and its metal complexes were evaluated for antimicrobial activity against gram-positive bacteria (S. aureus), gram-negative bacteria (E. coli), and fungi (C. albicans and A. flavus). The ligand and some of its complexes were biologically active; the copper complexes bound to DNA via an intercalation binding mode with intrinsic binding constants (Kb) of 1.3 to 2.5 3 104 M1. AMPs have been widely studied as a potential class of antibiotics for treating infectious diseases caused by MDR bacterial strains and have been recognized as potential substitutes for common antibiotics used in pig feeds (124). With broad-spectrum activity, AMPs can physically destroy the microbial membrane and may be a promising approach to supersede antibacterial chemicals. A natural AMP, indolicidin, and a more potent synthetic dendrimeric analog generated hydroxide radicals in target bacterial cells via the Fenton reaction (65). Because AMPs are refractory to bacterial resistance, unlike the bactericidal antibiotics tested, researchers hypothesized that the source of the OH radicals differed from that in bactericidal antibiotics. Four peptides (derived from barley, soybean, a-casein, and a-zein) with known antihypertensive activity were evaluated for antimicrobial activity against four pathogenic microorganisms: E. coli, S. aureus, Micrococcus luteus, and C. albicans (73). The peptides TTMPLW and PGTAVFK inhibited growth of all four microorganisms tested, with activity of a similar order of magnitude as that of ampicillin. Among the alanine analogues studied, PGAAVFK had the highest antimicrobial activity. Overall, food-derived peptides may exert beneficial effects via a number of mechanisms. Structural flexibility was the most important mechanism of antimicrobial activity for AMPs, similar to hydrophobicity and electronic charge (47). Defined as a weighted average of amino acid flexibility indices over the whole residue chain of AMP, the flexibility index was used to scale the peptide flexibility as an indication of mechanical properties such as tensile and flexural rigidities. The results indicated that the flexibility index is relevant to but different from other structural properties; it may enhance activity against E. coli for stiff clustered peptides or reduce activity against E. coli for flexible clustered peptides. Its optimum value is about 0.5. The effect of flexibility on antimicrobial activity may involve the stable peptide-bound leaflet formation and subsequent mechanical stress in the target cell membrane. These results provide new insight into antimicrobial actions and may be useful for seeking a new structure-activity relationship for cationic and amphipathic a-helical peptides. The cyclic lipopeptides surfactins and fengycins interfered with bacterial adhesion and biofilm formation of E. coli and S. aureus (39), indicating an additional means of inactivating these microorganisms. Filamentous temperature-sensitive protein Z (FtsZ), a prokaryotic cytoskeleton protein that plays an important role in bacterial cell division, has garnered special attention in the field of antibacterial research (64). The function and dynamic behaviors of FtsZ have been studied, and the natural and synthetic inhibitors of FtsZ also are known. A silica-protein hybrid material was prepared by simultaneous covalent deposition of apoferritin and lactoferrin on

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functionalized silica (18). This material has high antibacterial activity against E. coli because of its high iron-uptake capacity. Cathepsin K is a cysteine protease that has recently been identified as playing a functional role in chronic inflammatory responses (106). Rectal administration of recombinant cathepsin K in mice ameliorated the severity of intestinal inflammation, indicating direct bactericidal activity against intestinal bacteria. The b-barrel assembly machinery complex drives the assembly of b-barrel proteins into the outer membrane of gram-negative bacteria (116). Mastoparan-B isolated from the venom of the hornet Vespa basalis (126) had significantly different antimicrobial activity against two E. coli strains, Staphylococcus xylosus, and Citrobacter koseri at low dosages. Hydrophobicity modification of mastoparan-B by a single amino acid substitution of tryptophan for leucine enhanced the antimicrobial activity against Klebsiella pneumoniae, Salmonella Typhimurium, and Salmonella Choleraesuis. Mastoparan-B and its substitution analogs had no detrimental effects on beneficial probiotics.

MECHANISMS OF ANTIMICROBIAL ACTIVITY Amphotericin-B binds with ergosterol in fungal cell membranes to form a channel that leaks monovalent ions (Kþ, Naþ, Hþ, and Cl), primarily leading to fungal cell death (12). Amikacin works by binding to the bacterial 30S ribosomal subunit, causing misreading of mRNA and leaving the bacterium unable to synthesize proteins vital to its growth (32). Amoxicillin acts as other b-lactams by inhibiting the cross-linkage between the linear peptidoglycan polymer chains that make up the cell walls of both grampositive and gram-negative bacteria (42). A better understanding of antimicrobial mechanisms at the molecular level can be obtained by identifying the evolution of resistance mechanisms and elucidating the various ways in which these mechanisms spread among bacteria. Research on how bacteria adapt to changing environments underlies the contemporary biological understanding of signal transduction (68); researchers are learning more about bacterial behavior so bacterial signals can be mimicked or blocked. Although the cell surface and membrane are generally implicated in the antibacterial action of AMPs, a complete understanding of the detailed mechanisms involved is still lacking.

ANTIMICROBIAL ACTIVE PACKAGING, FILMS, AND COATINGS The utility of antimicrobial compounds against foodborne pathogens mainly involves food processing and active packaging. Antimicrobial agents are used in food processing plants to eliminate the growth of microorganisms that affect the quality and safety of the end products (3). Antimicrobial coating on food handling materials improves food safety by reducing cross-contamination from food processing equipment (14). Antimicrobial agents can be added to the food processing program as a processing aid, a secondary direct food additive, or a direct food additive (26). Historically, the direct addition of natural antimicrobial compounds to food is the most common method. Dipping, spraying, and coating of


food with active solutions currently occurs before packaging for meat, fish, dairy products, minimally processed fruit, vegetables, and cereal-based products (67). Antimicrobial agents can also be used in food packaging and on food contact surfaces (75). A comprehensive review of antimicrobial packaging technologies and their significant impact on food safety has recently been published (71). Antimicrobial packaging simply incorporates antimicrobial agents into a coating or polymer film to suppress the activity of targeted microorganisms (109). The packaging is used to extend the lag period and reduce the growth rate of microorganisms, resulting in a longer product shelf life. Natural antimicrobial active packaging is an emerging technology for fresh fish preservation in which a chemical compound of natural origin is purposely incorporated into a packaging material to be released onto the food surface to protect it from spoilage by foodborne microorganisms. Cinnamon essential oil is widely known for its antimicrobial activity against the fungi Penicillium commune and Eurotium amstelodami commonly found in bread products and has been incorporated into cassava starch films to develop an active packaging (107). All films containing different amounts of essential oils were effective against P. commune and E. amstelodami. Another active package was designed for the preservation of fresh farmed salmon sold in cubes or slices (22). The package comprised a rigid polypropylene–ethylene vinyl alcohol copolymer tray heat sealed with an active film lid in which carvacrol was incorporated as an antimicrobial agent. The agent migrated rapidly through the fish muscle, and its molecules had a low affinity for the food matrix. By modifying the thickness of the active film, maximum efficiency of an antimicrobial package can be obtained; adequate activity is achieved immediately after the packaging operation and is maintained at a constant level throughout the product shelf life. Other antimicrobial active packaging films have been prepared based on polyethylene terephthalate, incorporating lysozyme as the antimicrobial agent (25). Sol-gel dip coating allowed the uniform deposition of lysozyme in submicrometer thicknesses on the polyethylene terephthalate surface and did not lead to a loss of antimicrobial activity of the enzyme against Micrococcus lysodeikticus. Direct covalent linkage of quaternary ammonium salt was applied to prepare a series of contact active antimicrobial surfaces based on widely utilized materials (89). Formation of antimicrobial surfaces by coupling quaternary ammonium salt with polyvinyl alcohol, cellulose, and glass was achieved by one-step synthesis with no auxiliary linkers. X-ray photoelectron spectroscopy revealed the tridentate binding mode of the antimicrobial agent. The antimicrobial activity of the prepared materials was tested on B. cereus, Alicyclobacillus acidoterrestris, E. coli, and P. aeruginosa. The active site density of the modified materials was correlated with their antimicrobial activity. Stability studies at different pH values and temperatures confirmed that the linkage of the bioactive moiety to the surface was robust. Long-term effectiveness of the contact active materials was indicated by their repeated usage without loss of the antimicrobial efficacy. Maillard reaction products have antimicrobial activity that is at least partially mediated by de novo generation of H2O2 (50). An



active Maillard reaction product fraction (16.1 g/liter) extracted from a ribose-lysine Maillard reaction mixture with 85% ethanol, completely inhibited the growth of E. coli for 24 h. This fraction was then incorporated in a polyvinyl acetate–based lacquer and dispersed onto a low-density polyethylene film. The coated film generated about 100 lM H2O2 and resulted in a .5-log reduction of E. coli. Thus, Maillard reaction products could be used as active ingredients for antimicrobial packaging materials during food storage. Bioactive packaging using natural biopolymers is of interest globally because of its environment-friendly nature. The weak mechanical and barrier properties of biopolymers can be significantly enhanced by nanocellulose fibers that can incorporate antimicrobials to extend the food shelf life and improve the food quality (56). The composites are cheap, lightweight, and very strong. The antimicrobial effect of a bioactive coating formulation was evaluated on broccoli florets inoculated with L. monocytogenes (100). Nanoemulsions of carvacrol, bergamot, lemon, and mandarin essential oils were incorporated in native and modified chitosan coating formulations. The modified chitosan coating containing mandarin essential oil caused a 1.46log reduction in L. monocytogenes after 6 days of storage. Higher antimicrobial activity was obtained in a treatment with the combined coating plus c-rays, which ensured microbial safety during storage with a 2.5-log reduction of L. monocytogenes after 13 days. Incorporating antimicrobial compounds into edible films or coatings provides a novel way to improve the safety of ready-to-eat foods. Pectin is a main component of the plant cell wall comprising poly-a-1,4-galacturonic acids. The U.S. Food and Drug Administration has listed pectin as generally recognized as safe, and this product is used as a gelling, stabilizing, or thickening agent in food products. Because of its biodegradability, biocompatibility, edibility, and versatile chemical and physical properties (such as selective gas permeability), pectin is a suitable polymeric edible film for active food packaging (36). Whey protein isolate edible coatings with oregano or clove essential oils incorporated as natural antimicrobial agents were developed to extend the shelf life of chicken breast (41). These insoluble, homogeneous, and continuous whey protein isolate coatings formed an imperceptible second skin covering the chicken breast. The antimicrobial effect of the coatings depended on their essential oil concentration (the higher the better), oil type (oregano oil was the most active), and the microbiological group analyzed (Pseudomonas spp. were the most resistant). Films with oregano oil doubled the storage time of chicken breast, keeping most of the microorganisms below the recommended limits for consumption of chicken breast. Whey protein isolate coatings as carriers of antimicrobial agents were more effective than the direct addition of essential oils to chicken breast surfaces. Edible methyl cellulose films with 1.5% marjoram achieved 6.3-, 4.5-, and 5.8-log reductions of the L. monocytogenes, E. coli, and S. aureus populations, respectively (101). Antimicrobial edible films also have been developed using defatted soybean meal, a lactoperoxidase system, and heat pressing (63). The

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lactoperoxidase plus defatted soybean meal film inhibited Salmonella Typhimurium by 1.5 log CFU per disk. The diffusion coefficient for antimicrobial hypothiocyanite in this film was 2 to 11 3 1015 m2/s, which increased with the water activity of the food or storage temperature. These results demonstrated the feasibility of producing edible films from defatted soybean meal on a large scale, and these films could be used as a food coating to deactivate Salmonella Typhimurium on food surfaces by controlled release of antimicrobial agents. Diverse studies with Quillaja saponaria (popularly called quillay) extracts have indicated their potential as antifungal agents against phytopathogenic fungi. Zún˜ iga et al. (131) evaluated the effect of ionizing radiation on extracts prepared from in vitro Q. saponaria plants to be used as antimicrobial agent (6% at minimum) in irradiated edible coating based on calcium caseinate and whey protein. Gamma irradiation above 15 kGy negatively affected the antimicrobial activity and the composition of the metabolites by reducing phenolic compounds. Otherwise, no effect on the saponin profile was observed. The researchers concluded that the antifungal activity of Q. saponaria extract is mainly related to the concentration of the phenolic compounds. Arrieta et al. (10) prepared active edible films by solvent casting after adding carvacrol into sodium and calcium caseinate matrices plasticized with glycerol. Carvacrol reduced the oxygen permeability and increase the surface hydrophobicity, and these biofilms had inhibitory effects on both E. coli and S. aureus. Nanostructured antimicrobial agents were reviewed for food packaging applications, including their mechanisms and scopes of action (29). Antimicrobial packaging films incorporating allyl isothiocyanate and carbon nanotubes were developed for shredded cooked chicken meat inoculated with Salmonella Choleraesuis (31). The carbon nanotubes were important for retaining the allyl isothiocyanate in the film. Diffusion of allyl isothiocyanate from the film into the chicken reduced microbial contamination and reduced color changes effectively during the 40 days of storage. A new antibacterial nanocomposite of copper nanoparticles embedded in polylactic acid film has been reported (66). The biodegradability of polylactic acid was used as a dynamic tool to release the antimicrobial metal ions. Silver nanoparticles (AgNPs) are well known for their antimicrobial properties that inhibit the growth of bacteria and viruses (128). AgNPs are incorporated into polymer nanocomposites because of their antimicrobial effect in food packaging. Composite films were prepared with AgNPs and agar (as a polymer matrix and a capping agent) (92). The agar films loaded with 1 to 2% (wt/wt) AgNPs exhibited strong antimicrobial activity against both grampositive (L. monocytogenes) and gram-negative (E. coli O157:H7) bacterial pathogens. However, migration of AgNPs from commercial plastic containers into the food has been revealed by scanning electron microscopy with energy dispersive X-ray spectroscopy (34). The total silver migration was 1.6 to 31 ng/cm2 (lower than the permissible limits). Antimicrobial bionanocomposite films have been prepared with gelatin, AgNPs, and

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organoclay (55). These films had high antibacterial activity against foodborne pathogens and could eliminate bacterial invaders and improve the shelf life of food. Ultimately, the cost consideration of implementing these interventions must include both the cost of the chemical product and the cost of the equipment required for implementation and future processing plant maintenance (85).


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CONCLUSIONS The global health crisis of antimicrobial resistance is linked to the administration of antimicrobial drugs to food animals for growth promotion and disease prevention. The study of antimicrobial resistant foodborne microorganisms should continue with advanced scientific and industrial technologies. Issues for researchers to consider include expanded surveillance for drug-resistant bacteria in factory farms, earlier intervention against antimicrobial resistance in agrifood systems, intensified research on bacterial resistance to third-generation cephalosporin antibiotics, enhanced genetic engineering for manufacturing antibiotics, more national promotion of investment in drug discovery, and better alternatives to antibiotics for the prevention of animal diseases. The American Society for Microbiology 4th Conference on Antimicrobial Resistance in Zoonotic Bacteria and Foodborne Pathogens (9) took place in Washington, DC from 8 through 11 May 2015. Emphases were placed on computational biology, host adaptation, isolate-based inference, mathematical modelling, molecular typing, and whole genome sequencing. Rigorous discussion of key factors that drive science policy on economic, moral, and social issues is continuing. The hope is that a systematic approach to mitigation of antimicrobial resistance via effective regulations will be implemented with cooperation of all interested parties.

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ACKNOWLEDGMENTS This work was partly supported by the Natural Sciences and Engineering Research Council of Canada, grant 315574 to E. P. C. Lai and grant 341690 to T. J. Avis. Z. Iqbal thanks the Bangladesh Agricultural University for funding his study leave.

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Essential oils, a new horizon in combating bacterial antibiotic resistance.

Antimicrobial Drugs in Fighting against Antimicrobial Resistance.

Combating pathogenic microorganisms using plant-derived antimicrobials: a minireview of the mechanistic basis.

Antimicrobial resistance in India.

Antimicrobial Resistance in Agriculture.

Targets for Combating the Evolution of Acquired Antibiotic Resistance.

Clinical relevance of molecular identification of microorganisms and detection of antimicrobial resistance genes in bloodstream infections of paediatric cancer patients.

Antibiotic resistance and burden of foodborne diseases in developing countries.

Antimicrobial susceptibility and antibiotic resistance gene transfer analysis of foodborne, clinical, and environmental Listeria spp. isolates including Listeria monocytogenes.

Antimicrobial Effects of Garcinia Mangostana on Cariogenic Microorganisms.

HIV.

Antimicrobial activity of Microgard against food spoilage and pathogenic microorganisms.

Homeopathy and antimicrobial resistance.

Antimicrobial resistance: challenges ahead.

Antimicrobial resistance: what's needed.

Antimicrobial resistance among enterococci.

Gonococcal antimicrobial resistance.