Quantitative measurement of antibiotic resistance in Mycobacterium tuberculosis reveals genetic determinants of resistance and susceptibility in a target gene approach
Zankin A., Clifton D., Crook D., Earle S., Fowler P., Giberto Cruz A., Hoosdally S., Knaggs J., Hunt M., Kouchaki S., Lachapelle A., Peto T., Rodger G., Roohi A., Thwaites G., Walker AS., Wilson D., Yang Y.
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 resulting in hypersensitivity. Our results advance genetics-based diagnostics for tuberculosis and serve as a curated training/testing dataset for development of drug resistance prediction algorithms.