Bedquiline Resistance Mutations: Correlations with Drug Exposures and Impact on the Proteome in M. tuberculosis.

Bedaquiline (BDQ) is an effective drug for the treatment of drug-resistant tuberculosis. Mutations in , which encodes the target of BDQ, are associated with large increases in MICs. Mutations in that derepress the transcription of the MmpL5-MmpS5 efflux transporter are associated with smaller increases in MICs. However, mutations are the most common mutations that are associated with BDQ resistance in clinical isolates, and they also confer cross-resistance to clofazimine (CFZ). To investigate the mechanism of BDQ resistance and the correlation between mutations and target-based mutations, M. tuberculosis strains were exposed to different concentrations of BDQ or CFZ to select mutations and mutations. Gene overexpression strains were constructed to illustrate the roles of MmpL5 and MmpS5. A quantitative proteome analysis was performed to compare the BDQ-resistant mutants to the isogenic strain H37Rv. Here, we report that the mutations were more readily selected than were the mutations at low concentrations of BDQ or CFZ. The mutations were selected by high concentrations of BDQ exposure. The overexpression of both and reduced the susceptibility of Mycobacterium tuberculosis to BDQ and CFZ. Secreted immunogenic proteins and proteins involved in the biosynthesis and transport of phthiocerol dimycocerosates were associated with mutations conferring BDQ resistance in the proteome analysis. In conclusion, exposure to different bedaquiline concentrations resulted in the selection of different mutations. The coexpression of MmpL5 and MmpS5 contributed to drug resistance and upregulated pathogenic proteins in M. tuberculosis, suggesting MmpL5-MmpS5 as a new potential target for antituberculosis drug development. These results warrant further surveillance for the evolution of BDQ resistance during clinical usage.