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.

authors

Lun S,Tasneen R,Chaira T,Stec J,Onajole OK,Yang TJ,Cooper CB,Mdluli K,Converse PJ,Nuermberger EL,Raj VS,Kozikowski A,Bishai WR

doi

10.1128/AAC.00343-19

subject

Has Abstract

pub_date

2019-06-24 00:00:00

issue

7

eissn

0066-4804

issn

1098-6596

pii

AAC.00343-19

journal_volume

63

pub_type

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