@article{3cdeb685453845f1af98a100dd0696f9,
title = "Advancing the therapeutic potential of indoleamides for tuberculosis",
abstract = "Indole-2-carboxamide derivatives are inhibitors of MmpL3, the cell wall-associated mycolic acid transporter of Mycobacterium tuberculosis. In the present study, we characterized indoleamide effects on bacterial cell morphology and reevaluated pharmacokinetics and in vivo efficacy using an optimized oral formulation. Morphologically, indoleamide-treated M. tuberculosis cells demonstrated significantly higher numbers of dimples near the poles or septum, which may serve as the mechanism of cell death for this bactericidal scaffold. Using the optimized formulation, an expanded-spectrum indoleamide, compound 2, showed significantly improved pharmacokinetic (PK) parameters and in vivo efficacy in mouse infection models. In a comparative study, compound 2 showed superior efficacy over compound 3 (NITD-304) in a high-dose aerosol mouse infection model. Since indoleamides are equally active on drug-resistant M. tuberculosis, these findings demonstrate the therapeutic potential of this novel scaffold for the treatment of both drug-susceptible and drug-resistant tuberculosis.",
keywords = "Chemotherapy, Indole-2-carboxamide, MmpL3 inhibitor, Mouse model, Mycobacterium tuberculosis, Mycolic acid",
author = "Shichun Lun and Rokeya Tasneen and Tridib Chaira and Jozef Stec and Onajole, {Oluseye K.} and Yang, {Tian J.} and Cooper, {Christopher B.} and Khisi Mdluli and Paul Converse and Nuermberger, {Eric L.} and {Samuel Raj}, V. and Alan Kozikowski and Bishai, {William R.}",
note = "Funding Information: This work was supported by TB Alliance with support from Australia{\textquoteright}s Department of Foreign Affairs and Trade, the Bill & Melinda Gates Foundation (OPP1129600), Irish Aid, Netherlands Ministry of Foreign Affairs, United Kingdom Department for International Development, and United Kingdom Department of Health. NIH funding grants AI37856 and HL133190 to W.R.B. supported this work, along with additional support from the TB Alliance to E.L.N. Funding Information: We thank Nader Fotouhi of TB Alliance for his critical discussion. This work was supported by TB Alliance with support from Australia{\textquoteright}s Department of Foreign Affairs and Trade, the Bill & Melinda Gates Foundation (OPP1129600), Irish Aid, Netherlands Ministry of Foreign Affairs, United Kingdom Department for International Development, and United Kingdom Department of Health. NIH funding grants AI37856 and HL133190 to W.R.B. supported this work, along with additional support from the TB Alliance to E.L.N. Publisher Copyright: Copyright {\textcopyright} 2019 Lun et al.",
year = "2019",
doi = "10.1128/AAC.00343-19",
language = "English (US)",
volume = "63",
journal = "Antimicrobial agents and chemotherapy",
issn = "0066-4804",
publisher = "American Society for Microbiology",
number = "7",
}