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

Abstract

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.

Keywords: ATP synthase; Russia; antimicrobial resistance; atpE; bacteria; bedaquiline; determinants of resistance; drug-resistant tuberculosis; mmpL3-mmpL4 efflux; tuberculosis and other mycobacteria.

Figure 1

Mapping of the candidate substitution Asn722Thr on the atomic model of Mycobacterium smegmatis MmpL5 transporter (PDB: 9B46) in study of high prevalence of atpE mutations in bedaquiline-resistant M. tuberculosis isolates, Russia. The proposed channel inlet is indicated on the surface model of the MmpL5. The channel model (olive) is shown on the cartoon model of the MmpL5 fragment. Red coloring and text indicates Ala774, located in the transmembrane domain TM8. Green text indicates residues and numbering for M. tuberculosis.

Figure 2

Mapping of the candidate substitution Val165Ile in AtpB on the atomic model of Mycobacterium tuberculosis ATP synthase (PDB: 8J0S) in study of high prevalence of atpE mutations in bedaquiline-resistant M. tuberculosis isolates, Russia. Identical c subunits of the rotor (encoded by the atpE gene) are shown with distinct colors.