Bacterial Genome-Wide Association Identifies Novel Factors That Contribute to Ethionamide and Prothionamide Susceptibility in Mycobacterium tuberculosis

Phenotypic antibiotic susceptibility testing in Mycobacterium tuberculosis is slow and cumbersome. Rapid molecular diagnostics promise to help guide therapy, but such assays rely on complete knowledge of the molecular determinants of altered antibiotic susceptibility. Recent genomic studies of antibiotic-resistant M. tuberculosis have identified several candidate loci beyond those already known to contribute to antibiotic resistance; however, efforts to provide experimental validation have lagged. Our study identifies a gene (Rv0565c) that is associated with resistance to the second-line antibiotic ethionamide at a population level. We then use bacterial genetics to show that the variants found in clinical strains of M. tuberculosis improve bacterial survival after ethionamide exposure.