Identification of Novel Imidazo[1,2-a]pyridine Inhibitors Targeting M. tuberculosis QcrB

被引:158
作者
Abrahams, Katherine A. [1 ]
Cox, Jonathan A. G. [1 ]
Spivey, Vickey L. [1 ]
Loman, Nicholas J. [1 ]
Pallen, Mark J. [1 ]
Constantinidou, Chrystala [1 ]
Fernandez, Raquel [2 ]
Alemparte, Carlos [2 ]
Remuinan, Modesto J. [2 ]
Barros, David [2 ]
Ballell, Lluis [2 ]
Besra, Gurdyal S. [1 ]
机构
[1] Univ Birmingham, Sch Biosci, Birmingham, W Midlands, England
[2] GlaxoSmithKline, Dis Dev World, Madrid, Spain
来源
PLOS ONE | 2012年 / 7卷 / 12期
基金
欧盟第七框架计划;
关键词
CYTOCHROME BC(1) COMPLEX; DRUG-RESISTANT TUBERCULOSIS; ANTITUBERCULAR DRUG; RESPIRATORY-CHAIN; QUINOL OXIDATION; ATP HOMEOSTASIS; DISCOVERY; MUCIDIN; LIBRARY; GENES;
D O I
10.1371/journal.pone.0052951
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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 mu M against a panel of M. tuberculosis strains. M. bovis BCG spontaneous resistant mutants were generated against IP 1, 3, and 4 at 56 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 mu M for IP 3. An acute murine model of TB infection established bacteriostatic activity of the IP series, which await further detailed characterization.
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页数:10
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