Journal Article

Identification of Novel Imidazo1,2-apyridine Inhibitors Targeting M. tuberculosis QcrB

Fernández, Raquel, Remuiñán, Modesto J., Barros, David, Ballell, Lluis, Spivey, Vickey L., Constantinidou, Chrystala, Alemparte, Carlos, Besra, Gurdyal S., Abrahams, Katherine A., Cox, Jonathan A. G., Pallen, Mark J., Loman, Nicholas J.

2012

Overview

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 (937)ACC>(937)GCC (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.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Alkaloids / Analysis / Animal models / Animals / Antibacterial agents / Antitubercular Agents - chemical synthesis / Antitubercular Agents - pharmacology / Antitubercular Agents - therapeutic use / Bacillus Calmette-Guerin vaccine / BCG / Binding sites / Biology / Chemistry / Cross-resistance / Cytochrome / Cytochrome c / DNA sequencing / Dogs / Drug resistance / Drug therapy / Electron transport / Gene dosage / Gene sequencing / Genomes / Genomics / Health aspects / HIV / Human immunodeficiency virus / Humans / Inhibitors / Lung diseases / Medical treatment / Medicine / Mice / Microbial Sensitivity Tests / Microsomes, Liver - drug effects / Minimum inhibitory concentration / Mutants / Mutation / Mycobacterium bovis - drug effects / Mycobacterium tuberculosis / Mycobacterium tuberculosis - drug effects / Overexpression / Polymorphism / Pyridine / Pyridines / Pyridines - antagonists & inhibitors / Rats / Reductase / Resistant mutant / Single nucleotide polymorphisms / Single-nucleotide polymorphism / Tuberculosis / Tuberculosis - drug therapy / Tuberculosis - prevention & control / Ubiquinol