Identification of novel imidazo[1,2-a]pyridine inhibitors targeting M. tuberculosis QcrB.

KA Abrahams, JA Cox, VL Spivey, NJ Loman, MJ Pallen, C Constantinidou, R Fernández, C Alemparte, MJ Remuiñán, D Barros, L Ballell, GS Besra

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Abstract

Mycobacterium tuberculosis is a major human pathogen and the causative agent for the pulmonary disease, tuberculosis (TB). Current treatment programs to combat TB are under threat due to the emergence of multi-drug and extensively-drug resistant TB. Through the use of high throughput whole cell screening of an extensive compound library a number of imidazo[1,2-a]pyridine (IP) compounds were obtained as potent lead molecules active against M. tuberculosis and Mycobacterium bovis BCG. The IP inhibitors (1–4) demonstrated minimum inhibitory concentrations (MICs) in the range of 0.03 to 5 µM against a panel of M. tuberculosis strains. M. bovis BCG spontaneous resistant mutants were generated against IP 1, 3, and 4 at 5× MIC and subsequent whole genome sequencing identified a single nucleotide polymorphism 937ACC>937GCC (T313A) in qcrB, which encodes the b subunit of the electron transport ubiquinol cytochrome C reductase. This mutation also conferred cross-resistance against IP 1, 3 and 4 demonstrating a common target. Gene dosage experiments confirmed M. bovis BCG QcrB as the target where over-expression in M. bovis BCG led to an increase in MIC from 0.5 to >8 µM for IP 3. An acute murine model of TB infection established bacteriostatic activity of the IP series, which await further detailed characterization.
Original languageEnglish
Article numbere52951
JournalPLoS ONE
Volume7
Issue number12
DOIs
Publication statusPublished - 31 Dec 2012

Bibliographical note

© 2012 Abrahams et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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    Abrahams, KA., Cox, JA., Spivey, VL., Loman, NJ., Pallen, MJ., Constantinidou, C., Fernández, R., Alemparte, C., Remuiñán, MJ., Barros, D., Ballell, L., & Besra, GS. (2012). Identification of novel imidazo[1,2-a]pyridine inhibitors targeting M. tuberculosis QcrB. PLoS ONE, 7(12), [e52951]. https://doi.org/10.1371/journal.pone.0052951