title: Identification of novel imidazo[1,2-a]pyridine inhibitors targeting M. tuberculosis QcrB.
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 (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.
authors.affiliation: School of Biosciences, University of Birmingham, Edgbaston, Birmingham, United Kingdom.
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Abrahams
authors.forename: Jonathan A G
authors.initials: JA
authors.lastname: Cox
authors.forename: Vickey L
authors.initials: VL
authors.lastname: Spivey
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Loman
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Pallen
authors.forename: Chrystala
authors.initials: C
authors.lastname: Constantinidou
authors.forename: Raquel
authors.initials: R
authors.lastname: Fernández
authors.forename: Carlos
authors.initials: C
authors.lastname: Alemparte
authors.forename: Modesto J
authors.initials: MJ
authors.lastname: Remuiñán
authors.forename: David
authors.initials: D
authors.lastname: Barros
authors.forename: Lluis
authors.initials: L
authors.lastname: Ballell
authors.forename: Gurdyal S
authors.initials: GS
authors.lastname: Besra
mesh_terms: D000818:Animals; D000995:Antitubercular Agents / Q000138:chemical synthesis / Q000494:pharmacology* / Q000627:therapeutic use; D004285:Dogs; D006801:Humans; D051379:Mice; D008826:Microbial Sensitivity Tests; D008862:Microsomes, Liver / Q000187:drug effects; D009163:Mycobacterium bovis / Q000187:drug effects*; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D011725:Pyridines / Q000037:antagonists & inhibitors*; D051381:Rats; D014376:Tuberculosis / Q000188:drug therapy* / Q000517:prevention & control
chemical_list: D000995:Antitubercular Agents; D011725:Pyridines; C001439:imidazo(1,2-a)pyridine