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Mutations in the F420 biosynthetic pathway and a nitroreductase enzyme are the primary resistance determinants in PA-824 spontaneous mutants in Mycobacterium tuberculosis

Haver, Hana and Chua, Adeline and Ghode, Pramila Baban and Lakshminarayana, Suresh Bangalore and Singhal, Amit and Mathema, Barun and Wintjens, Rene and Bifani, Juan Pablo (2015) Mutations in the F420 biosynthetic pathway and a nitroreductase enzyme are the primary resistance determinants in PA-824 spontaneous mutants in Mycobacterium tuberculosis. Antimicrobial Agents and Chemotherapy, 59 (9). pp. 5316-5323. ISSN 0000-0000

Official URL: http://www.asm.org/

Abstract

The persistent threat of global tuberculosis (TB) beckons a scientific investment in new drugs for the effective treatment of disease. PA-824 is a bicyclic 4-nitroimidazole currently under phase II clinical trials for the treatment of multidrug resistant TB. As such, it is critical to examine the molecular basis of the drug interaction with Mycobacterium tuberculosis (Mtb). In the present study, we aimed to elucidate and characterize the genetic polymorphisms associated with PA-824 drug resistance in spontaneously selected Mtb mutants. Of the 221 independently selected PA-824 resistant Mtb mutants, we found that 83% harbor a mutation on one of five genes that have been previously implicated in the activation of PA-824: ddn (39%), fgd1 (5%), fbiA (16%), fbiB (2%), and fbiC (21%). Minimum inhibitory concentration (MIC99) tests indicated that disruption to any of these 5 genes led to decreased susceptibility to PA-824. The frequency of emergence of PA-824 resistance was concentration dependent and therefore necessitates careful consideration for appropriate dosing to optimize therapy and to thwart early emergence development of resistance.

Item Type: Article
Date Deposited: 12 Oct 2016 00:45
Last Modified: 12 Oct 2016 00:45
URI: https://oak.novartis.com/id/eprint/21579

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