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

Abstract Tuberculosis (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 p...

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Autores principales:	Paula J. Gómez-González, Joao Perdigao, Pedro Gomes, Zully M. Puyen, David Santos-Lazaro, Gary Napier, Martin L. Hibberd, Miguel Viveiros, Isabel Portugal, Susana Campino, Jody E. Phelan, Taane G. Clark
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/ac9e817153344e7a8338f0481094ec66
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spelling	oai:doaj.org-article:ac9e817153344e7a8338f0481094ec662021-12-02T17:18:21ZGenetic diversity of candidate loci linked to Mycobacterium tuberculosis resistance to bedaquiline, delamanid and pretomanid10.1038/s41598-021-98862-42045-2322https://doaj.org/article/ac9e817153344e7a8338f0481094ec662021-09-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-98862-4https://doaj.org/toc/2045-2322Abstract Tuberculosis (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.Paula J. Gómez-GonzálezJoao PerdigaoPedro GomesZully M. PuyenDavid Santos-LazaroGary NapierMartin L. HibberdMiguel ViveirosIsabel PortugalSusana CampinoJody E. PhelanTaane G. ClarkNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-13 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Paula J. Gómez-González Joao Perdigao Pedro Gomes Zully M. Puyen David Santos-Lazaro Gary Napier Martin L. Hibberd Miguel Viveiros Isabel Portugal Susana Campino Jody E. Phelan Taane G. Clark Genetic diversity of candidate loci linked to Mycobacterium tuberculosis resistance to bedaquiline, delamanid and pretomanid
description	Abstract Tuberculosis (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.
format	article
author	Paula J. Gómez-González Joao Perdigao Pedro Gomes Zully M. Puyen David Santos-Lazaro Gary Napier Martin L. Hibberd Miguel Viveiros Isabel Portugal Susana Campino Jody E. Phelan Taane G. Clark
author_facet	Paula J. Gómez-González Joao Perdigao Pedro Gomes Zully M. Puyen David Santos-Lazaro Gary Napier Martin L. Hibberd Miguel Viveiros Isabel Portugal Susana Campino Jody E. Phelan Taane G. Clark
author_sort	Paula J. Gómez-González
title	Genetic diversity of candidate loci linked to Mycobacterium tuberculosis resistance to bedaquiline, delamanid and pretomanid
title_short	Genetic diversity of candidate loci linked to Mycobacterium tuberculosis resistance to bedaquiline, delamanid and pretomanid
title_full	Genetic diversity of candidate loci linked to Mycobacterium tuberculosis resistance to bedaquiline, delamanid and pretomanid
title_fullStr	Genetic diversity of candidate loci linked to Mycobacterium tuberculosis resistance to bedaquiline, delamanid and pretomanid
title_full_unstemmed	Genetic diversity of candidate loci linked to Mycobacterium tuberculosis resistance to bedaquiline, delamanid and pretomanid
title_sort	genetic diversity of candidate loci linked to mycobacterium tuberculosis resistance to bedaquiline, delamanid and pretomanid
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/ac9e817153344e7a8338f0481094ec66
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Genetic diversity of candidate loci linked to Mycobacterium tuberculosis resistance to bedaquiline, delamanid and pretomanid

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