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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.

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