In vitro approaches for generation of Mycobacterium tuberculosis mutants resistant to bedaquiline, clofazimine or linezolid and identification of associated genetic variants

dc.contributor.authorIsmail, Nazir Ahmed
dc.contributor.authorOmar, Shaheed Vally
dc.contributor.authorIsmail, Nabila
dc.contributor.authorPeters, Remco P.H.
dc.date.accessioned2019-03-08T08:11:20Z
dc.date.issued2018-10
dc.description.abstractBedaquiline, clofazimine and linezolid are pertinent drugs for drug-resistant tuberculosis. Drug-resistant mutants provide insight into important resistance acquisition mechanisms. Methods for in vitro Mycobacterium tuberculosis mutant generation are poorly described. Induction (serial passaging) and spontaneous (adapted Luria-Delbrück assay) approaches using M. tuberculosis ATCC reference strains (one fully-susceptible, four unique mono-resistant) were performed. Mutant MIC values were confirmed (MGIT960) and resultant RAVs compared between approaches and to a catalog of previously published RAVs. Mutant MIC values showed a 3–4-fold (induced) and a 1–4-fold (spontaneous) increase compared to baseline. The pyrazinamide-resistant strain had higher baseline MIC values and acquired resistance (≥4-fold) in fewer passages than other strains (induction approach) for bedaquiline. Previously described and novel RAVs in atpE (8 vs. 1) and rv0678 (4 vs. 12) genes were identified in bedaquiline- and clofazimine-resistant mutants. No rv1979c and rv2535c RAVs were identified. Previously described RAVs were identified in rplC and rrl genes for linezolid-resistant mutants. Both approaches successfully led to in vitro mutants with novel RAVs being described in atpE and rv0678 genes. It was observed that pre-existing resistance may influence mutant phenotypic and genotypic characteristics and warrants further attention.en_ZA
dc.description.departmentMedical Microbiologyen_ZA
dc.description.embargo2019-10-01
dc.description.librarianhj2019en_ZA
dc.description.sponsorshipNabila Ismail received PhD support from The National Research Fund (SFH150723130071) and the University of Pretoria.en_ZA
dc.description.urihttp://www.elsevier.com/ locate/jmicmethen_ZA
dc.identifier.citationIsmail, N., Omar, S.V., Ismail, N.A. et al. 2018, 'In vitro approaches for generation of Mycobacterium tuberculosis mutants resistant to bedaquiline, clofazimine or linezolid and identification of associated genetic variants', Journal of Microbiological Methods, vol. 153, pp. 1-9.en_ZA
dc.identifier.issn0167-7012 (print)
dc.identifier.issn1872-8359 (online)
dc.identifier.other10.1016/j.mimet.2018.08.011
dc.identifier.urihttp://hdl.handle.net/2263/68614
dc.language.isoenen_ZA
dc.publisherElsevieren_ZA
dc.rights© 2018 Elsevier B.V. All rights reserved. Notice : this is the author’s version of a work that was accepted for publication in Journal of Microbiological Methods. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. A definitive version was subsequently published in Journal of Microbiological Methods, vol. 153, pp. 1-9, 2018. doi : 10.1016/j.mimet.2018.08.011.en_ZA
dc.subjectMutantsen_ZA
dc.subjectBedaquilineen_ZA
dc.subjectClofazimineen_ZA
dc.subjectIn vitroen_ZA
dc.subjectMycobacterium tuberculosis (MTB)en_ZA
dc.subjectLinezoliden_ZA
dc.titleIn vitro approaches for generation of Mycobacterium tuberculosis mutants resistant to bedaquiline, clofazimine or linezolid and identification of associated genetic variantsen_ZA
dc.typePostprint Articleen_ZA

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