Mutations in the Esx-3 secretion system confer resistance to multiple chemical scaffolds in Mycobacterium tuberculosis

We determined the mechanism of resistance to seven chemical series with potent activity against <i>Mycobacterium tuberculosis</i>. Resistant mutants were isolated against the aminothiazoles, phenylhydrazones, 8-hydroxyquinolines, nitazoxanides, phenyl alkylimidazoles, morpholino thiophenes and trifluoromethyl pyrimidinones. We demonstrated that mutations in several components of the Esx-3 type VII secretion system (EccA3, EccB3, EccC3 and EccD3) conferred resistance to these disparate scaffolds. We conclude that mutations in Esx-3 are a common mechanism of resistance to anti-tubercular agents, which may have clinical relevance for new drugs.