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Combating the Scourge of TB
Tuberculosis (TB) caused by the bacterium Mycobacterium tuberculosis (Mtb) continues to be an epidemic in many parts of the world. Resistance to multiple drugs and the emergence of the HIV epidemic have created new challenges in TB treatment. Drugs with new mechanisms of action and improved safety profiles are urgently needed to manage TB. To achieve this goal, Rao et al. screened a chemical library of nearly 2 million compounds for inhibitors of mycobacterial growth. Using phenotypic high-throughput screening, they identified a group of molecules called indolcarboxamides as a new class of antitubercular bactericidal agents. Several indolcarboxamide analogs were evaluated to optimize their activity against Mtb and improve their properties. Two lead candidates, NITD-304 and NITD-349, with promising in vivo pharmacokinetic profiles showed potent activity against both drug-sensitive and multidrug-resistant Mtb clinical isolates. Investigating the mechanism of action, the authors found that the molecular target of the indolcarboxamides was MmpL3, a protein that is essential for mycobacterial cell wall biosynthesis and growth. NITD-304 and NITD-349 were efficacious in treating Mtb infections in mouse models of acute and chronic TB with a favorable safety margin. NITD-304 and NITD-349 are promising new drug candidates for treating TB with the potential to help fill the gap in the global TB drug discovery portfolio.
- Copyright © 2013, American Association for the Advancement of Science
