SMARt-420

SMARt-420 is a preclinical small-molecule spiroisoxazoline designed to reverse ethionamide resistance in Mycobacterium tuberculosis by activating an alternative ethionamide bioactivation pathway regulated by the TetR-like transcriptional repressor EthR2, thereby bypassing resistance-conferring mutations in the classical EthA-mediated activation route.[1][7][13] By binding to EthR2 and inducing a conformational change that disrupts its DNA-binding ability, SMARt-420 derepresses expression of an alternative Baeyer-Villiger monooxygenase pathway, increasing intracellular ethionamide activation and restoring sensitivity in ethionamide-resistant multidrug-resistant tuberculosis strains in vitro and in mouse models.[1][7][10][13] The compound was discovered and characterized by academic and translational research groups working on tuberculosis resistance mechanisms and has been highlighted as a first-in-class example of “resistance-aborting” adjunctive therapy rather than a standalone antibiotic.[1][7][9][13]

Other names

Small Molecule Aborting Resistancespiroisoxazoline SMARt-420