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Genetic diversity of candidate loci linked to Mycobacterium tuberculosis resistance to bedaquiline, delamanid and pretomanid

2021-09-30Journal article Open access
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dc.contributor.authorGómez-González, Paula J.
dc.contributor.authorPerdigão, João
dc.contributor.authorGomes, Pedro
dc.contributor.authorPuyen, Zully M.
dc.contributor.authorSantos-Lazaro, David
dc.contributor.authorNapier, Gary
dc.contributor.authorHibberd, Martin L.
dc.contributor.authorViveiros, Miguel
dc.contributor.authorPortugal, Isabel
dc.contributor.authorCampino, Susana
dc.contributor.authorPhelan, Jody
dc.contributor.authorClark, Taane G.
dc.date.accessioned2023-08-25T18:30:39Z
dc.date.available2023-08-25T18:30:39Z
dc.date.issued2021-09-30
dc.date.updated2023-03-13T20:26:46Z
dc.description.abstractTuberculosis (TB), caused by Mycobacterium tuberculosis, is one of the deadliest infectious diseases worldwide. Multidrug and extensively drug-resistant strains are making disease control difficult, and exhausting treatment options. New anti-TB drugs bedaquiline (BDQ), delamanid (DLM) and pretomanid (PTM) have been approved for the treatment of multi-drug resistant TB, but there is increasing resistance to them. Nine genetic loci strongly linked to resistance have been identified (mmpR5, atpE, and pepQ for BDQ; ddn, fgd1, fbiA, fbiB, fbiC, and fbiD for DLM/PTM). Here we investigated the genetic diversity of these loci across >33,000 M. tuberculosis isolates. In addition, epistatic mutations in mmpL5-mmpS5 as well as variants in ndh, implicated for DLM/PTM resistance in M. smegmatis, were explored. Our analysis revealed 1,227 variants across the nine genes, with the majority (78%) present in isolates collected prior to the roll-out of BDQ and DLM/PTM. We identified phylogenetically-related mutations, which are unlikely to be resistance associated, but also high-impact variants such as frameshifts (e.g. in mmpR5, ddn) with likely functional effects, as well as non-synonymous mutations predominantly in MDR-/XDR-TB strains with predicted protein destabilising effects. Overall, our work provides a comprehensive mutational catalogue for BDQ and DLM/PTM associated genes, which will assist with establishing associations with phenotypic resistance; thereby, improving the understanding of the causative mechanisms of resistance for these drugs, leading to better treatment outcomes.pt_PT
dc.description.sponsorshipPJG-G is funded by an MRC-LID PhD studentship. JEP is funded by a Newton Institutional Links Grant (British Council, no. 261868591). TGC is funded by the Medical Research Council UK (Grant no. MR/M01360X/1, MR/N010469/1, MR/R025576/1, and MR/R020973/1) and BBSRC (Grant no. BB/R013063/1). SC is funded by Medical Research Council UK grants (ref. MR/M01360X/1, MR/R025576/1, and MR/R020973/1). JP is supported by the Portuguese FCT (ref. CEECIND/00394/2017). PG is the recipient of a PhD studentship from the Portuguese FCT (ref. 2020.05942.BD). The authors declare no conflicts of interest.pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationGómez-González PJ, Perdigao J, Gomes P, Puyen ZM, Santos-Lazaro D, Napier G, et al. Genetic diversity of candidate loci linked to Mycobacterium tuberculosis resistance to bedaquiline, delamanid and pretomanid. Sci Rep [Internet]. 30 de setembro de 2021;11(1):19431. Disponível em: https://www.nature.com/articles/s41598-021-98862-4pt_PT
dc.identifier.doi10.1038/s41598-021-98862-4pt_PT
dc.identifier.issn2045-2322
dc.identifier.slugcv-prod-2853891
dc.identifier.urihttp://hdl.handle.net/10451/59030
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherSpringer Naturept_PT
dc.relationNot Available
dc.relation.publisherversionhttps://www.nature.com/articles/s41598-021-98862-4pt_PT
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/pt_PT
dc.titleGenetic diversity of candidate loci linked to Mycobacterium tuberculosis resistance to bedaquiline, delamanid and pretomanidpt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.awardTitleNot Available
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/CEEC IND 2017/CEECIND%2F00394%2F2017%2FCP1476%2FCT0001/PT
oaire.citation.issue1pt_PT
oaire.citation.startPage19431pt_PT
oaire.citation.titleScientific Reportspt_PT
oaire.citation.volume11pt_PT
oaire.fundingStreamCEEC IND 2017
person.familyNameLucas Mota Perdigão
person.familyNameViveiros Bettencourt
person.familyNamePortugal
person.familyNameCampino Clark
person.familyNamePhelan
person.familyNameClark
person.givenNameJoão Ruben
person.givenNameMiguel
person.givenNameIsabel
person.givenNameSusana
person.givenNameJody
person.givenNameTaane
person.identifiero39byr4AAAAJ
person.identifier642245
person.identifier.ciencia-id991C-F26A-9843
person.identifier.ciencia-idDF17-B4BF-8756
person.identifier.ciencia-idE310-5746-C205
person.identifier.ciencia-idEF14-DC2D-A029
person.identifier.ciencia-idDD1B-2564-161C
person.identifier.orcid0000-0002-0339-1305
person.identifier.orcid0000-0001-9676-6251
person.identifier.orcid0000-0002-7843-0006
person.identifier.orcid0000-0003-1403-6138
person.identifier.orcid0000-0001-8323-7019
person.identifier.orcid0000-0001-8985-9265
person.identifier.scopus-author-id24723211800
person.identifier.scopus-author-id7003949212
person.identifier.scopus-author-id7403216793
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.nameFundação para a Ciência e a Tecnologia
rcaap.cv.cienciaid991C-F26A-9843 | João Ruben Lucas Mota Perdigão
rcaap.rightsopenAccesspt_PT
rcaap.typearticlept_PT
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