Recent Advances in Antituberculous Drug Development and Novel Drug Targets

Haruaki Tomioka, PhD; Yutaka Tatano, PhD; Ko Yasumoto, PhD; Toshiaki Shimizu, PhD

Disclosures

Expert Rev Resp Med. 2008;2(4):455-471. 

In This Article

Five-year View

Although the present review highlights promising drug targets in MTB organisms, the difficulties associated with strategies for developing anti-TB drugs based on new drug targets identified using the entire genome information are not small. In fact, various attempts to develop new antimicrobial drugs using such a strategy for other bacterial infections have failed during the past decade. However, it is still possible to develop novel and useful anti-tuberculous drugs if we continue our efforts to search for inhibitors of MTB drug targets in conjunction with 3D-QSAR studies, based on precise information on the stereochemical formula of the mycobacterial target proteins obtained by x-ray crystallographic analysis. Although crystallography has its limitations, for example the production of membrane proteins is usually difficult and not all proteins are readily crystallized, it is possible to employ nuclear magnetic resonance and homology modeling systems as alternative routes to structure-based design.[10] It is thus expected that such investigations will advance greatly in the coming 5years. In this context, it should be noted that, in most QSAR studies, the 'drug activity' of a given compound is usually represented by its 'in vitro activity against MTB growing extracellularly in medium'.[7] However, for the development of novel and unique anti-TB drugs, the 'drug activity' can be preferably represented by its inhibitory activity against mycobacterial gene products essential for the expression of virulence by MTB pathogens, thereby enabling them to replicate and persist in macrophage phagosomes. During the next 5 years, 3D-QSAR studies based on such a strategy will proceed rapidly and it appears that, sooner or later, we can synthesize very promising compounds with excellent antimicrobial activity and novel mechanisms of action against MTB organisms, which are actively replicating or persisting in macrophage phagosomes.

Some promising agents, including nitroimidazole compounds (PA-824 and OPC-67683) and diarylquinoline derivative TMC207 are currently under clinical study.[95] Within the next 5 years, the two nitroimidazoles will surely be approved for clinical use, although there are some difficulties that should be resolved before their approval. First, the mutagenic activity, especially that of PA-824, will continue to be a major obstacle to the development of anti-TB drugs. Second, the development of OPC-67683 has been hampered somewhat due to bioavailability problems. In addition, there appears to be a drug interaction with one of the drugs in the first-line regimen (RIF or PZA) that reduces blood levels of OPC-67683.[96]

TMC207 is the most promising agent, since its target in MTB organisms is very unique and it has a novel action mechanism. In a clinical study by McNeeley and Cavaleri, single escalating dose and 14-day multiple escalating dose studies in healthy human males did not demonstrate severe adverse effects [97]. However, TMC207 is metabolized by CYP and, therefore, it has a drug interaction with RIF, which lowers its blood levels by 50%.[98] It is not yet clear whether this problem can be overcome by dosing adjustments. Therefore, more research on the pharmacokinetics of the compound is needed to develop a safety profile in women, children and individuals coinfected with HIV or HCV and TB. However, this drug will surely be released as a unique anti-TB drug in the coming 5 years.

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