Detection of a historic reservoir of bedaquiline/clofazimine resistance-associated variants in Mycobacterium tuberculosis
Abstract Background 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) resista...
| Main Authors: | , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2024-02-01
|
| Series: | Genome Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13073-024-01289-5 |
| _version_ | 1797259112436727808 |
|---|---|
| author | Camus Nimmo Arturo Torres Ortiz Cedric C. S. Tan Juanita Pang Mislav Acman James Millard Nesri Padayatchi Alison D. Grant Max O’Donnell Alex Pym Ola B. Brynildsrud Vegard Eldholm Louis Grandjean Xavier Didelot François Balloux Lucy van Dorp |
| author_facet | Camus Nimmo Arturo Torres Ortiz Cedric C. S. Tan Juanita Pang Mislav Acman James Millard Nesri Padayatchi Alison D. Grant Max O’Donnell Alex Pym Ola B. Brynildsrud Vegard Eldholm Louis Grandjean Xavier Didelot François Balloux Lucy van Dorp |
| author_sort | Camus Nimmo |
| collection | DOAJ |
| description | Abstract Background 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 off-target resistance-associated variants (RAVs) in the mmpR5 gene (Rv0678), the regulator of an efflux pump, which can also confer cross-resistance to clofazimine, another TB drug. Methods We compiled a dataset of 3682 Mtb genomes, including 180 carrying variants in mmpR5, and its immediate background (i.e. mmpR5 promoter and adjacent mmpL5 gene), that have been associated to borderline (henceforth intermediate) or confirmed resistance to bedaquiline. We characterised the occurrence of all nonsynonymous mutations in mmpR5 in this dataset and estimated, using time-resolved phylogenetic methods, the age of their emergence. Results We identified eight cases where RAVs were present in the genomes of strains collected prior to the use of bedaquiline in TB treatment regimes. Phylogenetic reconstruction points to multiple emergence events and circulation of RAVs in mmpR5, some estimated to predate the introduction of bedaquiline. However, epistatic interactions can complicate bedaquiline drug-susceptibility prediction from genetic sequence data. Indeed, in one clade, Ile67fs (a RAV when considered in isolation) was estimated to have emerged prior to the antibiotic era, together with a resistance reverting mmpL5 mutation. Conclusions The presence of a pre-existing reservoir of Mtb strains carrying bedaquiline RAVs prior to its clinical use augments the need for rapid drug susceptibility testing and individualised regimen selection to safeguard the use of bedaquiline in TB care and control. |
| first_indexed | 2024-03-07T14:49:05Z |
| format | Article |
| id | doaj.art-e8f39fa5b02340b0906e696f01f2c0b9 |
| institution | Directory Open Access Journal |
| issn | 1756-994X |
| language | English |
| last_indexed | 2024-04-24T23:04:15Z |
| publishDate | 2024-02-01 |
| publisher | BMC |
| record_format | Article |
| series | Genome Medicine |
| spelling | doaj.art-e8f39fa5b02340b0906e696f01f2c0b92024-03-17T12:34:01ZengBMCGenome Medicine1756-994X2024-02-0116111510.1186/s13073-024-01289-5Detection of a historic reservoir of bedaquiline/clofazimine resistance-associated variants in Mycobacterium tuberculosisCamus Nimmo0Arturo Torres Ortiz1Cedric C. S. Tan2Juanita Pang3Mislav Acman4James Millard5Nesri Padayatchi6Alison D. Grant7Max O’Donnell8Alex Pym9Ola B. Brynildsrud10Vegard Eldholm11Louis Grandjean12Xavier Didelot13François Balloux14Lucy van Dorp15UCL Genetics Institute, University College LondonUCL Genetics Institute, University College LondonUCL Genetics Institute, University College LondonUCL Genetics Institute, University College LondonUCL Genetics Institute, University College LondonAfrica Health Research InstituteCAPRISA MRC-HIV-TB Pathogenesis and Treatment Research UnitAfrica Health Research InstituteCAPRISA MRC-HIV-TB Pathogenesis and Treatment Research UnitAfrica Health Research InstituteDivision of Infectious Diseases and Environmental Health, Norwegian Institute of Public HealthDivision of Infectious Diseases and Environmental Health, Norwegian Institute of Public HealthDivision of Infection and Immunity, University College LondonSchool of Life Sciences and Department of Statistics, University of WarwickUCL Genetics Institute, University College LondonUCL Genetics Institute, University College LondonAbstract Background 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 off-target resistance-associated variants (RAVs) in the mmpR5 gene (Rv0678), the regulator of an efflux pump, which can also confer cross-resistance to clofazimine, another TB drug. Methods We compiled a dataset of 3682 Mtb genomes, including 180 carrying variants in mmpR5, and its immediate background (i.e. mmpR5 promoter and adjacent mmpL5 gene), that have been associated to borderline (henceforth intermediate) or confirmed resistance to bedaquiline. We characterised the occurrence of all nonsynonymous mutations in mmpR5 in this dataset and estimated, using time-resolved phylogenetic methods, the age of their emergence. Results We identified eight cases where RAVs were present in the genomes of strains collected prior to the use of bedaquiline in TB treatment regimes. Phylogenetic reconstruction points to multiple emergence events and circulation of RAVs in mmpR5, some estimated to predate the introduction of bedaquiline. However, epistatic interactions can complicate bedaquiline drug-susceptibility prediction from genetic sequence data. Indeed, in one clade, Ile67fs (a RAV when considered in isolation) was estimated to have emerged prior to the antibiotic era, together with a resistance reverting mmpL5 mutation. Conclusions The presence of a pre-existing reservoir of Mtb strains carrying bedaquiline RAVs prior to its clinical use augments the need for rapid drug susceptibility testing and individualised regimen selection to safeguard the use of bedaquiline in TB care and control.https://doi.org/10.1186/s13073-024-01289-5TuberculosisPhylogeneticsBedaquilineDrug resistanceAMR |
| spellingShingle | Camus Nimmo Arturo Torres Ortiz Cedric C. S. Tan Juanita Pang Mislav Acman James Millard Nesri Padayatchi Alison D. Grant Max O’Donnell Alex Pym Ola B. Brynildsrud Vegard Eldholm Louis Grandjean Xavier Didelot François Balloux Lucy van Dorp Detection of a historic reservoir of bedaquiline/clofazimine resistance-associated variants in Mycobacterium tuberculosis Genome Medicine Tuberculosis Phylogenetics Bedaquiline Drug resistance AMR |
| title | Detection of a historic reservoir of bedaquiline/clofazimine resistance-associated variants in Mycobacterium tuberculosis |
| title_full | Detection of a historic reservoir of bedaquiline/clofazimine resistance-associated variants in Mycobacterium tuberculosis |
| title_fullStr | Detection of a historic reservoir of bedaquiline/clofazimine resistance-associated variants in Mycobacterium tuberculosis |
| title_full_unstemmed | Detection of a historic reservoir of bedaquiline/clofazimine resistance-associated variants in Mycobacterium tuberculosis |
| title_short | Detection of a historic reservoir of bedaquiline/clofazimine resistance-associated variants in Mycobacterium tuberculosis |
| title_sort | detection of a historic reservoir of bedaquiline clofazimine resistance associated variants in mycobacterium tuberculosis |
| topic | Tuberculosis Phylogenetics Bedaquiline Drug resistance AMR |
| url | https://doi.org/10.1186/s13073-024-01289-5 |
| work_keys_str_mv | AT camusnimmo detectionofahistoricreservoirofbedaquilineclofazimineresistanceassociatedvariantsinmycobacteriumtuberculosis AT arturotorresortiz detectionofahistoricreservoirofbedaquilineclofazimineresistanceassociatedvariantsinmycobacteriumtuberculosis AT cedriccstan detectionofahistoricreservoirofbedaquilineclofazimineresistanceassociatedvariantsinmycobacteriumtuberculosis AT juanitapang detectionofahistoricreservoirofbedaquilineclofazimineresistanceassociatedvariantsinmycobacteriumtuberculosis AT mislavacman detectionofahistoricreservoirofbedaquilineclofazimineresistanceassociatedvariantsinmycobacteriumtuberculosis AT jamesmillard detectionofahistoricreservoirofbedaquilineclofazimineresistanceassociatedvariantsinmycobacteriumtuberculosis AT nesripadayatchi detectionofahistoricreservoirofbedaquilineclofazimineresistanceassociatedvariantsinmycobacteriumtuberculosis AT alisondgrant detectionofahistoricreservoirofbedaquilineclofazimineresistanceassociatedvariantsinmycobacteriumtuberculosis AT maxodonnell detectionofahistoricreservoirofbedaquilineclofazimineresistanceassociatedvariantsinmycobacteriumtuberculosis AT alexpym detectionofahistoricreservoirofbedaquilineclofazimineresistanceassociatedvariantsinmycobacteriumtuberculosis AT olabbrynildsrud detectionofahistoricreservoirofbedaquilineclofazimineresistanceassociatedvariantsinmycobacteriumtuberculosis AT vegardeldholm detectionofahistoricreservoirofbedaquilineclofazimineresistanceassociatedvariantsinmycobacteriumtuberculosis AT louisgrandjean detectionofahistoricreservoirofbedaquilineclofazimineresistanceassociatedvariantsinmycobacteriumtuberculosis AT xavierdidelot detectionofahistoricreservoirofbedaquilineclofazimineresistanceassociatedvariantsinmycobacteriumtuberculosis AT francoisballoux detectionofahistoricreservoirofbedaquilineclofazimineresistanceassociatedvariantsinmycobacteriumtuberculosis AT lucyvandorp detectionofahistoricreservoirofbedaquilineclofazimineresistanceassociatedvariantsinmycobacteriumtuberculosis |