In 2012, WHO estimated that there were 8.6 million new cases of TB globally (13% co-infected with HIV) resulting in 1.3 million deaths. In addition, MDR-TB and XDR-TB are significant public health threats. Emergence of drug-resistant strains of Mtb makes many of the currently available anti-TB drugs powerless. Thus, there is an urgent need to develop new-generation anti-TB drugs with novel target to counter the bacterial resistance.  FtsZ, bacterial homolog of tubulin, is a highly conserved and ubiquitous bacterial protein, playing an essential role in bacterial cytokinesis. The inhibition of proper FtsZ assembly causes the disruption of bacterial cell division, leading to cell lethality. Accordingly, Mtb-FtsZ inhibitors have a high potential to be next-generation anti-TB agents. Since FtsZ is an unexploited target for current antimicrobials, FtsZ inhibitors are active against clinical isolates of Mtb strains with various drug-resistance profile. This salient feature is highly promising against not only MDR-TB strains but also XDR-TB and TDR-TB strains. We have designed and synthesized novel classes of taxanes as well as benzimidazoles for creation of compound libraries as new chemical entities (NCEs) (>2,500 compounds). We have been leading the investigation in this field of research through productive collaboration with the Mycobacteria Research Laboratory, Colorado State University, as well as the Infectious Diseases Research Division of Sanofi. Two advanced lead benzimidazoles exhibited remarkable efficacy in the acute infection model using C57BL/6 mice via i.p. as well as p.o. route at 100 mg/kg dose/day for 10 days. SB-BI-38 reduced the bacterial load by 6.2 log10 CFU in lung and 4.0 log10 CFU in spleen (virtually no live bacterial counts) via p.o. route. SB-BI-42 was slightly less potent than SB-BI-38 in lung, but equally effective in spleen. The drug discovery and preclinical drug development of the next-generation anti-TB agents in our laboratory will be presented.

New generation anti-TB drug discovery targeting <i>Mtb</i>-FtsZ

248th National Meeting (2014)

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New generation anti-TB drug discovery targeting Mtb-FtsZ