Journal
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
Volume 63, Issue 7, Pages -Publisher
AMER SOC MICROBIOLOGY
DOI: 10.1128/AAC.00343-19
Keywords
MmpL3 inhibitor; Mycobacterium tuberculosis; chemotherapy; indole-2-carboxamide; mouse model; mycolic acid
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Funding
- Australia's Department of Foreign Affairs and Trade
- Bill & Melinda Gates Foundation [OPP1129600]
- Irish Aid
- Netherlands Ministry of Foreign Affairs
- United Kingdom Department for International Development
- United Kingdom Department of Health
- NIH [AI37856, HL133190]
- TB Alliance
- Bill and Melinda Gates Foundation [OPP1129600] Funding Source: Bill and Melinda Gates Foundation
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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.
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