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- Title
Identification of Novel Imidazo[1,2-a]pyridine Inhibitors Targeting M. tuberculosis QcrB.
- Authors
Abrahams, Katherine A.; Cox, Jonathan A. G.; Spivey, Vickey L.; Loman, Nicholas J.; Pallen, Mark J.; Constantinidou, Chrystala; Fernández, Raquel; Alemparte, Carlos; Remuiñán, Modesto J.; Barros, David; Ballell, Lluis; Besra, Gurdyal S.
- 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.
- Subjects
MYCOBACTERIUM tuberculosis; LUNG diseases; IMIDAZOLES; DRUG resistance in microorganisms; PYRIDINE
- Publication
PLoS ONE, 2012, Vol 7, Issue 12, p1
- ISSN
1932-6203
- Publication type
Article
- DOI
10.1371/journal.pone.0052951