Whole-genome sequencing of Mycobacterium tuberculosis for prediction of drug resistance

Abstract Whole-genome sequencing (WGS) has shown tremendous potential in rapid diagnosis of drug-resistant tuberculosis (TB). In the current study, we performed WGS on drug-resistant Mycobacterium tuberculosis isolates obtained from Shanghai ( n = 137) and Russia ( n = 78). We aimed to characterise the underlying and high-frequency novel drug-resistance-conferring mutations, and also create valuable combinations of resistance mutations with high predictive sensitivity to predict multidrug- and extensively drug-resistant tuberculosis (MDR/XDR-TB) phenotype using a bootstrap method. Most strains belonged to L2.2, L4.2, L4.4, L4.5 and L4.8 lineages. We found that WGS could predict 82.07% of phenotypically drug-resistant domestic strains. The prediction sensitivity for rifampicin (RIF), isoniazid (INH), ethambutol (EMB), streptomycin (STR), ofloxacin (OFL), amikacin (AMK) and capreomycin (CAP) was 79.71%, 86.30%, 76.47%, 88.37%, 83.33%, 70.00% and 70.00%, respectively. The mutation combination with the highest sensitivity for MDR prediction was rpoB S450L + rpoB H445A/P + katG S315T + inhA I21T + inhA S94A, with a sensitivity of 92.17% (0.8615, 0.9646), and the mutation combination with highest sensitivity for XDR prediction was rpoB S450L + katG S315T + gyrA D94G + rrs A1401G, with a sensitivity of 92.86% (0.8158, 0.9796). The molecular information presented here will be of particular value for the rapid clinical detection of MDR- and XDR-TB isolates through laboratory diagnosis.