High Prevalence of atpE Mutations in Bedaquiline-Resistant Mycobacterium tuberculosis Isolates, Russia

Bedaquiline is a cornerstone drug for treating drug-resistant tuberculosis. We analyzed 11 isolates from 9 patients who were treated with a bedaquiline-based regimen and remained culture-positive long after treatment start. In 4 of 8 resistant isolates, we found substitutions in AtpE, which encodes subunit c of the Mycobacterium tuberculosis ATP synthase and is rarely identified in clinical isolates. We found Ile66Met and Glu61Asp substitutions in 2 cases each. Additional mutations in mmpL5, mmpL4, and atpB genes could affect the susceptibility to bedaquiline. MmpL5(Asn772Thr) emerged during bedaquiline treatment, whereas AtpB(Val165Leu) was found in 1 case simultaneously with the loss-of-function mmpR5 mutation in a susceptible strain. The loss-of-function mutation in the mmpL4 efflux gene was identified in the mixed state, pointing to ongoing selection in a bedaquiline-resistant isolate. Another case of the emergence of the mmpL4 mutation, accompanied by a proportional increase in bedaquiline MIC, was identified by retrospective analysis of genomes from bedaquiline-resistant isolates.