Quantitative measurement of antibiotic resistance in Mycobacterium tuberculosis reveals genetic determinants of resistance and susceptibility in a target gene approach

The World Health Organization has a goal of universal drug susceptibility testing for patients with tuberculosis; however, molecular diagnostics to date have focused largely on first-line drugs and predicting binary susceptibilities. We used a multivariable linear mixed model alongside whole genome sequencing and a quantitative microtiter plate assay to relate genomic mutations to minimum inhibitory concentration in 15,211 Mycobacterium tuberculosis patient isolates from 23 countries across five continents. This identified 492 unique MIC-elevating variants across thirteen drugs, as well as 91 mutations likely linked to hypersensitivity. Our results advance genetics-based diagnostics for tuberculosis and serve as a curated training/testing dataset for development of drug resistance prediction algorithms.