The imidazopyridines are a promising new class of anti-tubercular agents with potent activity in vitro and in vivo. We isolated resistant mutants of Mycobacterium tuberculosis to a representative imidazopyridine; mutants had large shifts (>20-fold) in MIC (minimum inhibitory concentration). Whole genome sequencing revealed mutations in Rv1339, a hypothetical protein of unknown function. We isolated mutants to three further compounds from the series; mutants with single nucleotide polymorphisms in Rv1339 were isolated against two compounds. Mutants with single nucleotide polymorphisms in QcrB, the proposed target for this series, were isolated against one compound. All strains were resistant to two compounds, regardless of the mutation and a strain carrying the QcrB T313I mutation was resistant to all of the imidazopyridine derivatives tested, confirming cross-resistance. We confirmed that compounds from this series were targeting QcrB by monitoring pH homeostasis and ATP generation; imidazopyridines disrupted pH homeostasis and depleted ATP, providing further evidence of an effect on the electron transport chain. A representative compound was bacteriostatic against replicating bacteria, consistent with a mode of action against QcrB. The series had a narrow inhibitory spectrum, with no activity against other bacterial species. No synergy or antagonism was seen with other anti-tuberculosis drugs under development. In conclusion, our data support the hypothesis that the imidazopyridine series functions by reducing ATP generation via inhibition of QcrB.
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