Advancing the Therapeutic Potential of Indoleamides for Tuberculosis.

Journal:
Antimicrobial agents and chemotherapy, Volume: 63, Issue: 7
Published:
July 24, 2019
PMID:
31010860
Authors:
Shichun Lun S, Rokeya Tasneen R, Tridib Chaira T, Jozef Stec J, Oluseye K Onajole OK, Tian J Yang TJ, Christopher B Cooper CB, Khisi Mdluli K, Paul J Converse PJ, Eric L Nuermberger EL, V Samuel Raj VS, Alan Kozikowski A, William R Bishai WR
Abstract:

Indole-2-carboxamide derivatives are inhibitors of MmpL3, the cell wall-associated mycolic acid transporter of In the present study, we characterized indoleamide effects on bacterial cell morphology and reevaluated pharmacokinetics and efficacy using an optimized oral formulation. Morphologically, indoleamide-treated 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 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 , these findings demonstrate the therapeutic potential of this novel scaffold for the treatment of both drug-susceptible and drug-resistant tuberculosis.