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Detection of a reservoir of bedaquiline / clofazimine resistance associated variants in Mycobacterium tuberculosis predating the antibiotic era

Van Dorp, Lucy; Nimmo, Camus; Ortiz, Arturo Torres; Pang, Juanita; Acman, Mislav; Tan, Cedric CS; Millard, James; ... Balloux, François; + view all (2023) Detection of a reservoir of bedaquiline / clofazimine resistance associated variants in Mycobacterium tuberculosis predating the antibiotic era. BioRxiv: Cold Spring Harbor, NY, USA. Green open access

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Abstract

Drug resistance in tuberculosis (TB) poses a major ongoing challenge to public health. The recent inclusion of bedaquiline into TB drug regimens has improved treatment outcomes, but this advance is threatened by the emergence of strains of Mycobacterium tuberculosis (Mtb) resistant to bedaquiline. Clinical bedaquiline resistance is most frequently conferred by resistance-associated variants (RAVs) in the Rv0678 gene which can also confer cross-resistance to clofazimine, another TB drug. We compiled a dataset of 3,682 Mtb genomes, including 223 carrying Rv0678 bedaquiline RAVs. We identified at least 15 cases where RAVs were present in the genomes of strains collected prior to the use of bedaquiline in TB treatment regimes. Phylogenetic analyses point to multiple emergence events and circulation of RAVs in Rv0678, often prior to the introduction of bedaquiline or clofazimine. We also identify one case where the RAV Ile67fs is estimated to have emerged prior to the antibiotic era. The presence of a pre-existing reservoir of bedaquiline-resistant Mtb strains augments the need for rapid drug susceptibility testing and individualised regimen selection to safeguard the use of bedaquiline in TB care and control.

Type: Working / discussion paper
Title: Detection of a reservoir of bedaquiline / clofazimine resistance associated variants in Mycobacterium tuberculosis predating the antibiotic era
Open access status: An open access version is available from UCL Discovery
DOI: 10.1101/2020.10.06.328799
Publisher version: https://doi.org/10.1101/2020.10.06.328799
Language: English
Additional information: The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC 4.0 International license (https://creativecommons.org/licenses/by-nc/4.0/).
Keywords: Tuberculosis, phylogenetics, bedaquiline, drug resistance, AMR
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Genetics, Evolution and Environment
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Infection, Immunity and Inflammation Dept
URI: https://discovery.ucl.ac.uk/id/eprint/10174627
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