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The small-molecule SMARt751 reverses Mycobacterium tuberculosis resistance to ethionamide in acute and chronic mouse models of tuberculosis

The sensitivity of Mycobacterium tuberculosis, the pathogen that causes tuberculosis (TB), to antibiotic prodrugs is dependent on the efficacy of the activation process that transforms the prodrugs into their active antibacterial moieties. Various oxidases of M. tuberculosis have the potential to activate the prodrug ethionamide. Here, we used medicinal chemistry coupled with a phenotypic assay to select the N-acylated 4-phenylpiperidine compound series. The lead compound, SMARt751, interacted with the transcriptional regulator VirS of M. tuberculosis, which regulates the mymA operon encoding a monooxygenase that activates ethionamide. SMARt751 boosted the efficacy of ethionamide in vitro and in mouse models of acute and chronic TB. SMARt751 also restored full efficacy of ethionamide in mice infected with M. tuberculosis strains carrying mutations in the ethA gene, which cause ethionamide resistance in the clinic. SMARt751 was shown to be safe in tests conducted in vitro and in vivo. A model extrapolating animal pharmacokinetic and pharmacodynamic parameters to humans predicted that as little as 25 mg of SMARt751 daily would allow a fourfold reduction in the dose of ethionamide administered while retaining the same efficacy and reducing side effects. Description The small-molecule SMARt751 reverses M. tuberculosis resistance to ethionamide by up-regulating the mymA operon. Boosting the action of a TB drug Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis and is one of the leading causes of death from a single infectious agent. Ethionamide is a prodrug used to treat multidrug resistant TB. MymA is a mycobacterial oxidase that is responsible for the activation of ethionamide. The production of MymA is under the control of the transcriptional regulator VirS. Flipo et al. now report the discovery of the small-molecule SMARt751, a VirS ligand that up-regulates expression of the mymA operon. SMARt751 reversed resistance to ethionamide in mouse models of acute and chronic TB.