Challenges and Opportunities in Developing Novel Drugs for TB
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PERSPECTIVE SPECIAL FOCUS: NEGLECTED DISEASES For reprint orders, please contact [email protected] Challenges and opportunities in developing novel drugs for TB Mycobacterium tuberculosis is a difficult pathogen to combat and the first-line drugs currently in use are 40–60 years old. The need for new TB drugs is urgent, but the time to identify, develop and ultimately advance new drug regimens onto the market has been excruciatingly slow. On the other hand, the drugs currently in clinical development, and the recent gains in knowledge of the pathogen and the disease itself give us hope for finding new drug targets and new drug leads. In this article we highlight the unique biology of the pathogen and several possible ways to identify new TB chemical leads. The Global Alliance for TB Drug Development (TB Alliance) is a not-for-profit organization whose mission is to accelerate the discovery and development of new TB drugs. The organization carries out research and development in collaboration with many academic laboratories and pharmaceutical companies around the world. In this perspective we will focus on the early discovery phases of drug development and try to provide snapshots of both the current status and future prospects. Need for new drugs treatment be discontinued, the organisms will Takushi Kaneko†1, One point often overlooked regarding existing often rebound in numbers causing a relapse. As Christopher Cooper1 TB drugs is that the standard four-drug combi- discussed later, the pathogen Mtb is very well & Khisimuzi Mdluli1 nation is relatively inexpensive and works rea- adapted to human infection, and can gener- 1TB Alliance, 40 Wall Street, 24th sonably well in drug-sensitive (DS) TB patients. ally successfully evade the onslaught of human Floor, New York, NY 10005, USA †Author for correspondence: The four-drug combination (isoniazid, rifampin, immunological attacks. The reason for combin- Tel.: +1 646 616 8642 pyrazinamide and ethambutol; TABLE 1) given ing drugs is that resistant mutants will emerge E-mail: [email protected] daily over a period of 6 to 9 months can cure if only a single drug is used for a long period approximately 85% of DS TB patients if the treat- of time. The concept of TB drug combinations ment regimen is strictly followed [1]. Although was empirically reached in the 1960s, and, in cure rates as high as 95% have been reported, fact, these four first-line drugs and most of the they are not typically observed. If the cure rate is drugs in the second-line treatment are at least 85%, a follow-up question might be why TB still 40 years old. From the 1960s until the present kills 1.7–1.8 million people every year [2]. The time, very few new TB drugs were introduced most straightforward answer is that these drugs into the clinic. The second-line drugs include are far from ideal. However, the more complete amikacin, capreomycin, ciprofloxacin, ethion- answer is undoubtedly manifold and related to amide, cycloserine and p-aminosalicylic acid not only the current treatments but also rooted (TABLE 2). Second-line drugs, in general, tend to in socioeconomic factors. The almost univer- have more adverse effects, and a limited activ- sally accepted standard of care that involves long ity profile compared with first-line drugs. Some treatment times and multiple-drug combina- second-line agents, such as amikacin and cap- tions in treating TB patients attests to the fact reomycin, have to be given by injection, making that the current drugs are not exceedingly effica- administration for an extended duration more cious and TB’s propensity to develop resistance difficult especially in resource-restricted regions to any single agent requires the use of combina- of the world. As with other infectious diseases, it tion chemotherapy. The four-drug combination is inevitable that drug resistance occurs almost treatment includes 2 months of these four drugs immediately after a new agent is introduced to followed by 4 months of isoniazid and rifampin. clinic. Those strains of Mtb that are resistant to The reason for this long treatment period is that at least isoniazid and rifampin are termed mul- it is exceedingly difficult to entirely eliminate the tidrug resistant (MDR). For MDR-TB patients, causative pathogen, Mycobacterium tuberculosis the second-line drugs and/or other registered (Mtb), from a patient. Even if culture negativity antibiotics are empirically used for approxi- (i.e., the absence of Mtb in sputum) is achieved mately 12–18 months. In the past 5 years, Mtb in a period shorter than 6 months, should the strains resistant to at least isoniazid, rifampin, 10.4155/FMC.11.115 © 2011 Future Science Ltd Future Med. Chem. (2011) 3(11), 1373–1400 ISSN 1756-8919 1373 PERSPECTIVE | Kaneko, Cooper & Mdluli Table 1. First-line drugs. Name Structure Structure Mechanism of action number Isoniazid H 1 Cell wall (inhibition of O N NH2 InhA) N Rifampin (rifampicin) Me Me 2 RNA polymerase O HO Me Me O OH O OH OH Me Me Me MeO NH N O N O OH N O Me Me Pyrazinamide O 3 Multiple (including N intracellular acidification, NH 2 decrease of delta pH) N Ethambutol 4 Cell wall (inhibition of H HO N arabinosyl transferase) N OH H InhA: NADH-dependent enoyl-ACP reductase. fluoroquinolones and one of the second-line consensus that we need to find drugs that kill injectable agents have been discovered and such nonreplicating as well as replicating bacteria to strains have been defined as extensively drug achieve overall treatment shortening. Ideal new resistant (XDR). In addition, large numbers drugs should demonstrate a novel mechanism of TB patients are co-infected with HIV, ren- of action (MOA) to avoid existing anti-TB drug dering more complex their treatment for these resistance, and should be active against MDR two infections that both require combination and XDR strains. They should also be safe, well- therapy. Ideally, TB drugs used to treat HIV co- tolerated and possess ADME properties suitable infected individuals should have little potential for co-administration with anti-HIV agents and for drug–drug interaction with co-administered appropriate for oral dosing, optimally within a antiretroviral drugs. However, this is not always fixed-dose combination. It is also imperative that the case; one prominent example of an agent the drugs are available at relatively low cost, espe- causing drug–drug interactions is rifampin, cially if intended for DS TB patients in develop- which induces cytochrome P450 enzymes, lead- ing countries. The current cost of the first-line ing to a reduction in systemic exposure of some drugs is approximately US$20–40 for the full commonly used antiretroviral agents. course of treatment [1] and a new drug should The long treatment duration, emergence of not change this substantially. It is also desirable resistant strains, adverse effects from many of that the drug should be orally efficacious for the existing drugs, and the need for treating the ease of administration. Drugs intended for HIV–TB co-infected patients make it apparent MDR and XDR TB patients should attempt to that there is a desperate need for new TB drugs. meet the above characteristics but may be given Considering the attrition rate and the length of more leeway. drug development in general, the need for an Recent advances in the knowledge of the even larger assortment of new TB drug can- molecular biology of Mtb have been significant, didates is equally urgent. The ideal new agent as spearheaded by the whole genome sequenc- should be rapidly bactericidal (rather than bac- ing in 1998 [3]. More specifically, knowledge of teriostatic) and possess potent sterilizing activ- the complete Mtb genome sequence has enabled ity to enable a stable cure to be achieved in a the essentiality of genes to be established in vitro shorter time period than for the currently avail- and in vivo [4,5]; the use of genome-wide DNA able therapy. As discussed later, there is growing microarrays to study patterns of gene expression 1374 Future Med. Chem. (2011) 3(11) future science group Challenges & opportunities in developing novel drugs for TB | PERSPECTIVE Table 2. Second-line drugs. Class Name Structure Structure number Mechanism of action Aminoglycosides Kanamycin H2N 4 Protein synthesis HO O HO inhibition (binding to 16S HO NH subnit of rRNA) O 2 HO NH2 O R R' O OH NH2 Kanamycin A R=NH2, R'=OH Kanamycin B R=NH2, R'=NH2 Kanamycin C R=OH, R'=NH2 Amikacin H N 5 Protein synthesis 2 O HO inhibition (binding to 16S HO O HO NH subnit of rRNA) O 2 NH HO NH 2 O OH OH HO O OH NH2 Polypeptides Capreomycin R 6 Protein synthesis O O NH H 2 inhibition (inhibition of H N N NH 2 N N 2 translocation) H H O NH O H N H NH O N 2 O O H NH N NH H Capreomycin IA R=OH Capreomycin IB R=H Viomycin OH 7 Protein synthesis O H H inhibition (inhibition of N N H N 2 N OH translocation) H NH O O 2 NH O H H N NH O N 2 O O H NH HO N NH H Enviomycin OH 8 Protein synthesis OH O H H inhibition (inhibition of N N H2N N OH translocation) H NH O O 2 NH O H N H NH O N 2 O O H NH N NH H Fluoroquinolones Ciprofloxacin O 9 DNA synthesis inhibition F CO2H (inhibition of gyrase) N N HN InhA: NADH-dependent enoyl-ACP reductase. future science group www.future-science.com 1375 PERSPECTIVE | Kaneko, Cooper & Mdluli Table 2.