Variants in bedaquiline-candidate-resistance genes: prevalence in bedaquiline-naive patients, effect on MIC, and association with Mycobacterium tuberculosis lineage

Emmanuel Riviere, Lennert Verboven, Anzaan Dippenaar, Sander Goossens, Elise De Vos, Elizabeth Streicher, Bart Cuypers, Kris Laukens, Fathia Ben-Rached, Timothy C. Rodwell, Arnab Pain, Robin M. Warren, Tim H. Heupink, Annelies Van Rie

Research output: Contribution to journalA1: Web of Science-articlepeer-review

Abstract

Studies have shown that variants in bedaquiline-resistance genes can occur in isolates from bedaquiline-naive patients. We assessed the prevalence of variants in all bedaquiline-candidate-resistance genes in bedaquiline-naive patients, investigated the association between these variants and lineage, and the effect on phenotype. We used whole-genome sequencing to identify variants in bedaquiline-resistance genes in isolates from 509 bedaquiline treatment naive South African tuberculosis patients. A phylogenetic tree was constructed to investigate the association with the isolate lineage background. Bedaquiline MIC was determined using the UKMYC6 microtiter assay. Variants were identified in 502 of 509 isolates (98.6%), with the highest (85%) prevalence of variants in the Rv0676c ( mmpL5) gene. We identified 36 unique variants, including 19 variants not reported previously. Only four isolates had a bedaquiline MIC equal to or above the epidemiological cut-off value of 0.25 μg/mL. Phylogenetic analysis showed that 14 of the 15 variants observed more than once occurred monophyletically in one Mycobacterium tuberculosis (sub)lineage. The bedaquiline MIC differed between isolates belonging to lineage 2 and 4 (Fisher's exact test, P  = 0.0004). The prevalence of variants in bedaquiline-resistance genes in isolates from bedaquiline-naive patients is high, but very few (<2%) isolates were phenotypically resistant. We found an association between variants in bedaquiline resistance genes and Mycobacterium tuberculosis (sub)lineage, resulting in a lineage-dependent difference in bedaquiline phenotype. Future studies should investigate the impact of the presence of variants on bedaquiline-resistance acquisition and treatment outcome.

Original languageEnglish
JournalAntimicrobial Agents and Chemotherapy
Volume66
Issue number7
Pages (from-to)e0032222
Number of pages12
ISSN0066-4804
DOIs
Publication statusPublished - 2022

Keywords

  • Antitubercular Agents/pharmacology
  • Diarylquinolines/pharmacology
  • Humans
  • Microbial Sensitivity Tests
  • Mycobacterium tuberculosis/genetics
  • Phylogeny
  • Prevalence
  • Tuberculosis, Multidrug-Resistant/drug therapy

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