REVIEW
Opportunities and Challenges for Natural Products as Novel Antituberculosis Agents Shrouq I. Farah,1 Abd Almonem Abdelrahman,2 E. Jeffrey North,1 and Harsh Chauhan1 1
Department of Pharmacy Sciences, School of Pharmacy and Health Professions, Creighton University, Omaha, Nebraska. 2 Department of Internal Medicine, School of Medicine, Creighton University, Omaha, Nebraska.
ABSTRACT Current tuberculosis (TB) treatment suffers from complexity of the dosage regimens, length of treatment, and toxicity risks. Many natural products have shown activity against drug-susceptible, drug-resistant, and latent/dormant Mycobacterium tuberculosis, the pathogen responsible for TB infections. Natural sources, including plants, fungi, and bacteria, provide a rich source of chemically diverse compounds equipped with unique pharmacological, pharmacokinetic, and pharmacodynamic properties. This review focuses on natural products as starting points for the discovery and development of novel anti-TB chemotherapy and classifies them based on their chemical nature. The classes discussed are divided into alkaloids, chalcones, flavonoids, peptides, polyketides, steroids, and terpenes. This review also highlights the importance of collaboration between phytochemistry, medicinal chemistry, and physical chemistry, which is very important for the development of these natural compounds.
INTRODUCTION
I
n 1882, Robert Koch first identified Mycobacterium tuberculosis as the causative pathogen responsible for tuberculosis (TB). A little over a century later, the World Health Organization declared TB a global epidemic, due to the poor success of treatment and the high mortality rates associated with TB infections.1 Moreover, one-third of the global population carries the asymptomatic latent or dormant bacterial form, further increasing the risk for disease spreading among the population by increasing the risk of TB reactivation.1,2 In 2013, TB incidences were reported to be *9 million, where TB infections claimed 1.5 million lives.3 The current, short-course frontline TB therapy consists of rifampicin, isoniazid, ethambutol, and pyrazinamide cocktail for a 2-month ‘‘intensive phase,’’ followed by rifampicin and isoniazid administration for a 4-month ‘‘continuation phase’’ to
DOI: 10.1089/adt.2015.673
eradicate the latent bacilli. Except for bedaquiline, the Food and Drug Administration has not approved a new anti-TB drug in the last 40 years despite the current treatment suffering from significant shortcomings such as length of the dosage regimen, toxicity of antitubercular agents, and resistance development to currently used agents.4 Therefore, the need for novel anti-TB drugs is crucial. Mutations in at least 10 genes in the M. tuberculosis genome can cause the emergence of drug-resistant TB strains.5 Drug resistance has developed, in part, by patient noncompliance and drug shortages, which has forced the use of more toxic, less effective, and more expensive drugs for a longer treatment duration. Multidrug-resistant TB (MDR-TB) strains are resistant to two of the first-line antitubercular drugs, rifampicin and isoniazid. Extensively, drug-resistant TB (XDR-TB) strains are associated with high levels of mortality because these strains are resistant to the first-line antitubercular drugs, rifampicin and isoniazid, along with any of the fluoroquinolones and at least one of the injectable second-line antitubercular agents (capreomycin, kanamycin, and amikacin).6 Among the new TB cases and previously treated cases between 1997 and 2012, 15% and 45%, respectively, were patients infected with MDR strains. Among the drug-resistant cases, 11% were infected with the XDR strains.7 A meta-analysis study comprising 91,538 TB patients revealed that only 54% of TB treatments were successful, where 15% of that patient population died and 20% suffered from adverse effects,8 such as hepatic dysfunction, ocular complications, ototoxicity, and gastrointestinal side effects.9 The previous data emphasize the need for new treatment and diagnostic tools, as well as a programmatic follow-up for patients to identify infected patients and treat them in a timely manner while reducing the spread of the disease among the population.10 The ideal anti-TB drug must be potent, safe, easily administered, active against resistant strains, active against latent and replicating bacteria, and it should have a low incidence of drug/drug interactions.1 Table 1 describes the ideal attributes of an anti-TB drug. Several compounds in preclinical and clinical studies have been identified during the last few years for developing new TB treatment. These approaches include discovery of novel chemical entities, such as bedaquiline,11–13 PA-824,14–16 and
ª MARY ANN LIEBERT, INC. VOL. XX
NO. XX XXXX 2015 ASSAY and Drug Development Technologies
1
FARAH ET AL.
Table 1. Desired Properties of a New Antituberculosis Drug Attributes
Desired properties
Short treatment
Strong potent safe drugs with bactericidal activity
time
on latent or dormant or heterogeneous population
Treatment of
New class of chemicals with broad mechanism of
MDR-XDR
action as well as low toxicities
Available at
Easily available throughout the world
low price
Price appropriate in developing countries
Reduced pill
Combination of potent drugs to reduce the number
burden
of pills taken
anticancer to anti-inflammatory.29 However, long-term consumption in mice increases the risk of ulcers, cecum and colon inflammation, and thyroid gland follicular cell hyperplasia. Thus, promiscuity is a challenge for the development of natural products as drug leads.30 Recently, significant efforts have been made to explore and optimize various natural compounds for their antimycobacterial activities.31 Alkaloids Many anti-TB scaffolds are inspired by those of naturally occurring alkaloids.32 Tiliacorinine, 20 -nortiliacorinine, and
Child friendly dosage forms/delivery systems Reduced drug–drug
Minimal drug–drug interactions especially with drugs
interactions
for specific conditions like antivirals, anti-HIV, and antidiabetics
Lower dosing frequencies
Enhance bioavailability with longer retention potency Novel formulation and development technologies
MDR, multidrug resistant; XDR, extensively drug resistant.
delamanid,17,18 and the optimization and repurposing of old drugs, such as riminophenazines,19–21 b-lactams,22,23 and oxazolidinones24,25 for anti-TB activity. These approaches have been successful in introducing many promising lead compounds in preclinical and clinical studies. However, none of these compounds meet the requirements for an ideal anti-TB drug and they all have limitations to be successful antitubercular agents.26
NATURAL PRODUCTS: A POTENTIAL SOLUTION FOR TB CHALLENGES With the low output of lead compounds from highthroughput screening efforts, focus has shifted toward the exploration and development of natural products as effective antimicrobial drugs.27 Drugs from natural origin comprise *75% of all the antibacterial agents discovered between 1981 and 2010.28 The exploration of nature as a source of novel antimicrobial agents is expanding and they offer a remarkable opportunity to identify interesting chemical scaffolds for drug discovery by providing chemically diverse compounds. Many natural products have multiple activities against multiple targets, which may reduce drug-resistance rates since it is likely that multiple genetic mutations would be required. However, promiscuous compounds, whether natural or synthetic, have tendencies to be cytotoxic. Curcumin is an example of a natural product that has multiple direct molecular targets and many pharmacological activities ranging from
2 ASSAY and Drug Development Technologies XXXX 2015
Fig. 1. Tiliacorinine (1), 20 -nortiliacorinine (2), and tiliacorine (3) are bisbenzylisoquinoline alkaloids isolated from Tiliacora triandra roots. 130 -Bromo-tiliacorinine (4) is the synthetic derivative of Tiliacorinine. Compound (5) is the thioethyl analogue of ascididemin. Halicyclamine A (6) was isolated from Haliclona sp.
ª MARY ANN LIEBERT, INC.
NATURAL PRODUCTS FOR TUBERCULOSIS
Fig. 2. Chalcones (7 and 8) isolated from Helichrysum melanacme. Compound (9) is a peltogynan derivative.
tiliacorine are bisbenzylisoquinoline alkaloids isolated from Tiliacora triandra roots (compounds 1, 2, 3, and 4, respectively, Fig. 1). They were found to exhibit activity against isolated MDR-TB strains with minimum inhibitory concentration (MIC) values in the range of 3.1–6.2 mg/mL.33 Screening of the murine natural products library resulted in the identification of the pyridoacridone alkaloid ascididemin, which also blocks M. tuberculosis growth (MIC
Opportunities and Challenges for Natural Products as Novel Antituberculosis Agents Shrouq I. Farah,1 Abd Almonem Abdelrahman,2 E. Jeffrey North,1 and Harsh Chauhan1 1
Department of Pharmacy Sciences, School of Pharmacy and Health Professions, Creighton University, Omaha, Nebraska. 2 Department of Internal Medicine, School of Medicine, Creighton University, Omaha, Nebraska.
ABSTRACT Current tuberculosis (TB) treatment suffers from complexity of the dosage regimens, length of treatment, and toxicity risks. Many natural products have shown activity against drug-susceptible, drug-resistant, and latent/dormant Mycobacterium tuberculosis, the pathogen responsible for TB infections. Natural sources, including plants, fungi, and bacteria, provide a rich source of chemically diverse compounds equipped with unique pharmacological, pharmacokinetic, and pharmacodynamic properties. This review focuses on natural products as starting points for the discovery and development of novel anti-TB chemotherapy and classifies them based on their chemical nature. The classes discussed are divided into alkaloids, chalcones, flavonoids, peptides, polyketides, steroids, and terpenes. This review also highlights the importance of collaboration between phytochemistry, medicinal chemistry, and physical chemistry, which is very important for the development of these natural compounds.
INTRODUCTION
I
n 1882, Robert Koch first identified Mycobacterium tuberculosis as the causative pathogen responsible for tuberculosis (TB). A little over a century later, the World Health Organization declared TB a global epidemic, due to the poor success of treatment and the high mortality rates associated with TB infections.1 Moreover, one-third of the global population carries the asymptomatic latent or dormant bacterial form, further increasing the risk for disease spreading among the population by increasing the risk of TB reactivation.1,2 In 2013, TB incidences were reported to be *9 million, where TB infections claimed 1.5 million lives.3 The current, short-course frontline TB therapy consists of rifampicin, isoniazid, ethambutol, and pyrazinamide cocktail for a 2-month ‘‘intensive phase,’’ followed by rifampicin and isoniazid administration for a 4-month ‘‘continuation phase’’ to
DOI: 10.1089/adt.2015.673
eradicate the latent bacilli. Except for bedaquiline, the Food and Drug Administration has not approved a new anti-TB drug in the last 40 years despite the current treatment suffering from significant shortcomings such as length of the dosage regimen, toxicity of antitubercular agents, and resistance development to currently used agents.4 Therefore, the need for novel anti-TB drugs is crucial. Mutations in at least 10 genes in the M. tuberculosis genome can cause the emergence of drug-resistant TB strains.5 Drug resistance has developed, in part, by patient noncompliance and drug shortages, which has forced the use of more toxic, less effective, and more expensive drugs for a longer treatment duration. Multidrug-resistant TB (MDR-TB) strains are resistant to two of the first-line antitubercular drugs, rifampicin and isoniazid. Extensively, drug-resistant TB (XDR-TB) strains are associated with high levels of mortality because these strains are resistant to the first-line antitubercular drugs, rifampicin and isoniazid, along with any of the fluoroquinolones and at least one of the injectable second-line antitubercular agents (capreomycin, kanamycin, and amikacin).6 Among the new TB cases and previously treated cases between 1997 and 2012, 15% and 45%, respectively, were patients infected with MDR strains. Among the drug-resistant cases, 11% were infected with the XDR strains.7 A meta-analysis study comprising 91,538 TB patients revealed that only 54% of TB treatments were successful, where 15% of that patient population died and 20% suffered from adverse effects,8 such as hepatic dysfunction, ocular complications, ototoxicity, and gastrointestinal side effects.9 The previous data emphasize the need for new treatment and diagnostic tools, as well as a programmatic follow-up for patients to identify infected patients and treat them in a timely manner while reducing the spread of the disease among the population.10 The ideal anti-TB drug must be potent, safe, easily administered, active against resistant strains, active against latent and replicating bacteria, and it should have a low incidence of drug/drug interactions.1 Table 1 describes the ideal attributes of an anti-TB drug. Several compounds in preclinical and clinical studies have been identified during the last few years for developing new TB treatment. These approaches include discovery of novel chemical entities, such as bedaquiline,11–13 PA-824,14–16 and
ª MARY ANN LIEBERT, INC. VOL. XX
NO. XX XXXX 2015 ASSAY and Drug Development Technologies
1
FARAH ET AL.
Table 1. Desired Properties of a New Antituberculosis Drug Attributes
Desired properties
Short treatment
Strong potent safe drugs with bactericidal activity
time
on latent or dormant or heterogeneous population
Treatment of
New class of chemicals with broad mechanism of
MDR-XDR
action as well as low toxicities
Available at
Easily available throughout the world
low price
Price appropriate in developing countries
Reduced pill
Combination of potent drugs to reduce the number
burden
of pills taken
anticancer to anti-inflammatory.29 However, long-term consumption in mice increases the risk of ulcers, cecum and colon inflammation, and thyroid gland follicular cell hyperplasia. Thus, promiscuity is a challenge for the development of natural products as drug leads.30 Recently, significant efforts have been made to explore and optimize various natural compounds for their antimycobacterial activities.31 Alkaloids Many anti-TB scaffolds are inspired by those of naturally occurring alkaloids.32 Tiliacorinine, 20 -nortiliacorinine, and
Child friendly dosage forms/delivery systems Reduced drug–drug
Minimal drug–drug interactions especially with drugs
interactions
for specific conditions like antivirals, anti-HIV, and antidiabetics
Lower dosing frequencies
Enhance bioavailability with longer retention potency Novel formulation and development technologies
MDR, multidrug resistant; XDR, extensively drug resistant.
delamanid,17,18 and the optimization and repurposing of old drugs, such as riminophenazines,19–21 b-lactams,22,23 and oxazolidinones24,25 for anti-TB activity. These approaches have been successful in introducing many promising lead compounds in preclinical and clinical studies. However, none of these compounds meet the requirements for an ideal anti-TB drug and they all have limitations to be successful antitubercular agents.26
NATURAL PRODUCTS: A POTENTIAL SOLUTION FOR TB CHALLENGES With the low output of lead compounds from highthroughput screening efforts, focus has shifted toward the exploration and development of natural products as effective antimicrobial drugs.27 Drugs from natural origin comprise *75% of all the antibacterial agents discovered between 1981 and 2010.28 The exploration of nature as a source of novel antimicrobial agents is expanding and they offer a remarkable opportunity to identify interesting chemical scaffolds for drug discovery by providing chemically diverse compounds. Many natural products have multiple activities against multiple targets, which may reduce drug-resistance rates since it is likely that multiple genetic mutations would be required. However, promiscuous compounds, whether natural or synthetic, have tendencies to be cytotoxic. Curcumin is an example of a natural product that has multiple direct molecular targets and many pharmacological activities ranging from
2 ASSAY and Drug Development Technologies XXXX 2015
Fig. 1. Tiliacorinine (1), 20 -nortiliacorinine (2), and tiliacorine (3) are bisbenzylisoquinoline alkaloids isolated from Tiliacora triandra roots. 130 -Bromo-tiliacorinine (4) is the synthetic derivative of Tiliacorinine. Compound (5) is the thioethyl analogue of ascididemin. Halicyclamine A (6) was isolated from Haliclona sp.
ª MARY ANN LIEBERT, INC.
NATURAL PRODUCTS FOR TUBERCULOSIS
Fig. 2. Chalcones (7 and 8) isolated from Helichrysum melanacme. Compound (9) is a peltogynan derivative.
tiliacorine are bisbenzylisoquinoline alkaloids isolated from Tiliacora triandra roots (compounds 1, 2, 3, and 4, respectively, Fig. 1). They were found to exhibit activity against isolated MDR-TB strains with minimum inhibitory concentration (MIC) values in the range of 3.1–6.2 mg/mL.33 Screening of the murine natural products library resulted in the identification of the pyridoacridone alkaloid ascididemin, which also blocks M. tuberculosis growth (MIC
