Respiratory chain gene mutations associated with global phylogenetic clustering of drug-resistant Mycobacterium tuberculosis revealed by whole-genome sequencing

Background The regulatory mechanism of respiratory chain in Mycobacterium tuberculosis ( M. tuberculosis ) remains to be elucidated, and limited evidence about the effect of gene mutations in the respiratory chain on multidrug-resistant (MDR) isolates was reported. Objective To elucidated the effect of gene mutations in the respiratory chain on MDR isolates. Methods Whole-genome sequencing was performed on analyzed strains of M. tuberculosis . Random forest, gradient boosting decision tree and generalized linear mixed models were employed to identify mutations in respiratory chain genes that contribute to the phylogenetic clustering and development of MDR isolates. Results Overall, a total of 13402 isolates of M. tuberculosis were included in the study. 4051 (30.09%) isolates showed MDR, and 1044 (7.76%) isolates were classified as single‐drug resistance (SDR). The results showed that the single nucleotide polymorphisms (SNPs) of atpH A428G, cydA C942A, qcrA G181C, nuoF G66C, qcrB G1250T, nuoA G82C, and nuoG A1422G A1810G were significantly associated with phylogenetic clustering of MDR isolates. The SNPs of ndhA G1000A, atpH C73G A428G, cydA C942A, qcrA G181C, qcrB G55A, nuoG A1422G, nuoJ G115A, nuoN G1084T, cydB T126C, nuoA G82C, nuoB G490C, nuoF C171T, and nuoK C73T were significantly associated with formation of MDR isolates. Conclusion Our study proposed that SNPs in genes of the respiratory chain were related to the phylogenetic clustering and development of MDR isolates, which provides new insights for preventing the phylogenetic clustering and development of MDR isolates. These insights provide valuable information for the development of potential therapeutic targets for MDR isolates.