Acquired Mycobacterium tuberculosis resistance to the commonly used antibiotic ethionamide (ETH) is mediated by mutations in the bacterial enzymatic pathway that is required for biological activation of the drug. Here, Blondiaux et al. identify a series of spiroisoxazoline compounds — named small molecules aborting resistance (SMARt) — which trigger an alternative activation pathway for ETH. The combination of SMARt-420 plus ETH was active against a panel of drug-resistant clinical M. tuberculosis strains and in mice infected with an ETH-resistant strain of M. tuberculosis.