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

Autor:	Rivière E; Tuberculosis Omics Research Consortium, Family Medicine and Population Health, Faculty of Medicine and Health Sciences, University of Antwerpgrid.5284.b, Antwerp, Belgium.; Adrem Data Lab, Department of Computer Science, Faculty of Sciences, University of Antwerpgrid.5284.b, Antwerp, Belgium., Verboven L; Tuberculosis Omics Research Consortium, Family Medicine and Population Health, Faculty of Medicine and Health Sciences, University of Antwerpgrid.5284.b, Antwerp, Belgium.; Adrem Data Lab, Department of Computer Science, Faculty of Sciences, University of Antwerpgrid.5284.b, Antwerp, Belgium., Dippenaar A; Tuberculosis Omics Research Consortium, Family Medicine and Population Health, Faculty of Medicine and Health Sciences, University of Antwerpgrid.5284.b, Antwerp, Belgium., Goossens S; Tuberculosis Omics Research Consortium, Family Medicine and Population Health, Faculty of Medicine and Health Sciences, University of Antwerpgrid.5284.b, Antwerp, Belgium.; Adrem Data Lab, Department of Computer Science, Faculty of Sciences, University of Antwerpgrid.5284.b, Antwerp, Belgium., De Vos E; Tuberculosis Omics Research Consortium, Family Medicine and Population Health, Faculty of Medicine and Health Sciences, University of Antwerpgrid.5284.b, Antwerp, Belgium., Streicher E; Division of Molecular Biology and Human Genetics, South African Medical Research Council Centre for Tuberculosis Research, DSI-NRF Centre of Excellence for Biomedical Tuberculosis Research, Faculty of Medicine and Health Sciences, Stellenbosch Universitygrid.11956.3a, Cape Town, South Africa., Cuypers B; Adrem Data Lab, Department of Computer Science, Faculty of Sciences, University of Antwerpgrid.5284.b, Antwerp, Belgium.; Molecular Parasitology, Department of Biomedical Sciences, Institute of Tropical Medicine, Antwerp, Belgium., Laukens K; Adrem Data Lab, Department of Computer Science, Faculty of Sciences, University of Antwerpgrid.5284.b, Antwerp, Belgium., Ben-Rached F; Computational Bioscience Research Centre, Biological Environmental Sciences and Engineering Division, King Abdullah University of Science and Technologygrid.45672.32, Thuwal, Saudi Arabia., Rodwell TC; FIND, Geneva, Switzerland.; Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of California San Diego, La Jolla, California, USA., Pain A; Computational Bioscience Research Centre, Biological Environmental Sciences and Engineering Division, King Abdullah University of Science and Technologygrid.45672.32, Thuwal, Saudi Arabia.; International Institute for Zoonosis Control, Hokkaido University, Sapporo, Hokkaido, Japan., Warren RM; Division of Molecular Biology and Human Genetics, South African Medical Research Council Centre for Tuberculosis Research, DSI-NRF Centre of Excellence for Biomedical Tuberculosis Research, Faculty of Medicine and Health Sciences, Stellenbosch Universitygrid.11956.3a, Cape Town, South Africa., Heupink TH; Tuberculosis Omics Research Consortium, Family Medicine and Population Health, Faculty of Medicine and Health Sciences, University of Antwerpgrid.5284.b, Antwerp, Belgium., Van Rie A; Tuberculosis Omics Research Consortium, Family Medicine and Population Health, Faculty of Medicine and Health Sciences, University of Antwerpgrid.5284.b, Antwerp, Belgium.
Jazyk:	angličtina
Zdroj:	Antimicrobial agents and chemotherapy [Antimicrob Agents Chemother] 2022 Jul 19; Vol. 66 (7), pp. e0032222. Date of Electronic Publication: 2022 Jun 27.
DOI:	10.1128/aac.00322-22
Abstrakt:	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.
Databáze:	MEDLINE
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