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Indolcarboxamide Is a Preclinical Candidate for Treating Multidrug-Resistant Tuberculosis

2013; American Association for the Advancement of Science; Volume: 5; Issue: 214 Linguagem: Inglês

10.1126/scitranslmed.3007355

1946-6242

Srinivasa P. S. Rao, Suresh B. Lakshminarayana, Ravinder Reddy Kondreddi, Maxime Hervé, Luis R. Camacho, Pablo Bifani, Sarath K. Kalapala, Jan Jiřiček, Leong L. Ng, Bee Huat Tan, Seow Hwee Ng, Mahesh Nanjundappa, Sindhu Ravindran, Peck Gee Seah, Pamela Thayalan, Siao H. Lim, Boon H. Lee, Anne Goh, Whitney Barnes, Zhong Chen, Kerstin Gagaring, Arnab K. Chatterjee, Kévin Pethe, Kelli Kuhen, John R. Walker, Feng Gu, Sreehari Babu, Lijun Zhang, Francesca Blasco, David Beer, Margaret L. Weaver, Véronique Dartois, Richard Glynne, Thomas Dick, Paul W. Smith, Thierry T. Diagana, Ujjini H. Manjunatha,

Cancer therapeutics and mechanisms

New chemotherapeutic compounds against multidrug-resistant Mycobacterium tuberculosis (Mtb) are urgently needed to combat drug resistance in tuberculosis (TB). We have identified and characterized the indolcarboxamides as a new class of antitubercular bactericidal agent. Genetic and lipid profiling studies identified the likely molecular target of indolcarboxamides as MmpL3, a transporter of trehalose monomycolate that is essential for mycobacterial cell wall biosynthesis. Two lead candidates, NITD-304 and NITD-349, showed potent activity against both drug-sensitive and multidrug-resistant clinical isolates of Mtb. Promising pharmacokinetic profiles of both compounds after oral dosing in several species enabled further evaluation for efficacy and safety. NITD-304 and NITD-349 were efficacious in treating both acute and chronic Mtb infections in mouse efficacy models. Furthermore, dosing of NITD-304 and NITD-349 for 2 weeks in exploratory rat toxicology studies revealed a promising safety margin. Finally, neither compound inhibited the activity of major cytochrome P-450 enzymes or the hERG (human ether-a-go-go related gene) channel. These results suggest that NITD-304 and NITD-349 should undergo further development as a potential treatment for multidrug-resistant TB.