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Identification of novel Imidazo[1,2-a]pyridine inhibitors targeting M. tuberculosis QcrB
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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 and Besra, Gurdyal S. (2012) Identification of novel Imidazo[1,2-a]pyridine inhibitors targeting M. tuberculosis QcrB. PLoS One, Volume 7 (Number 12). Article number e52951. doi:10.1371/journal.pone.0052951 ISSN 1932-6203.
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Official URL: http://dx.doi.org/10.1371/journal.pone.0052951
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.
| Item Type: | Journal Article | ||||
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| Subjects: | R Medicine > R Medicine (General) R Medicine > RA Public aspects of medicine > RA0421 Public health. Hygiene. Preventive Medicine |
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| Divisions: | Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School > Biomedical Sciences > Microbiology & Infection Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School |
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| Library of Congress Subject Headings (LCSH): | Tuberculosis, Tuberculosis -- Microbiology, Mycobacterium tuberculosis, Bacterial genetics | ||||
| Journal or Publication Title: | PLoS One | ||||
| Publisher: | Public Library of Science | ||||
| ISSN: | 1932-6203 | ||||
| Official Date: | 2012 | ||||
| Dates: |
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| Volume: | Volume 7 | ||||
| Number: | Number 12 | ||||
| Page Range: | Article number e52951 | ||||
| DOI: | 10.1371/journal.pone.0052951 | ||||
| Status: | Peer Reviewed | ||||
| Publication Status: | Published | ||||
| Access rights to Published version: | Open Access (Creative Commons) | ||||
| Date of first compliant deposit: | 26 December 2015 | ||||
| Date of first compliant Open Access: | 26 December 2015 | ||||
| Funder: | Royal Society (Great Britain). Wolfson Research Merit Award (RSWRMA), Seventh Framework Programme (European Commission) (FP7) | ||||
| Grant number: | 261378 (FP7) |
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