Variants in Bedaquiline-Candidate-Resistance Genes: Prevalence in Bedaquiline-Naive Patients, Effect on MIC, and Association with Mycobacterium tuberculosis Lineage

Emmanuel Rivière, 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 journalArticlepeer-review

2 Scopus citations

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 (
Original languageEnglish (US)
JournalAntimicrobial Agents and Chemotherapy
DOIs
StatePublished - Jun 27 2022

Bibliographical note

KAUST Repository Item: Exported on 2022-06-29
Acknowledgements: K.L. reports funding by Janssen, Pharmaceutical Companies of Johnson & Johnson. T.C.R. reports funding by FIND (Geneva, Switzerland) and NIH/NIAD (grant number R21AI135756) and is coinventor on a patent associated with the processing of sequencing files (European Patent Application No. 14840432.0 & USSN 14/912,918) and a provisional patent for a TB diagnostic assay (USSN Provisional Patent No. 63/048.989). R.M.W. reports baseline funding of the South African Medical Research Council. A.V.R. reports funding by Research Foundation Flanders (grant number G0F8316N).
This work was supported by the Research Foundation Flanders (FWO), under FWO Odysseus (grant number G0F8316N) and FWO Strategic Basic Research (grant number 1S39119N), the NRF, the SAMRC, and the Stellenbosch University Faculty of Medicine Health Sciences. The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Research Foundation (NRF) or the South African Medical Research Council (SAMRC). Library preparations and sequencing for 80% of isolates were done at the sequencing facility of Macrogen in Seoul, Korea. The remainder were sequenced through existing collaborations with the Translational Genomics Research Institute (David Engelthaler), Centers for Disease Control and Prevention (James Posey), University of California San Diego (Timothy C. Rodwell), FIND (Timothy C. Rodwell), and the Institute of Infectious Disease and Molecular Medicine (Helen Cox).

ASJC Scopus subject areas

  • Infectious Diseases
  • Pharmacology
  • Pharmacology (medical)

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