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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 (\n                    <jats:italic>mmpR5<\/jats:italic>\n                    ,\n                    <jats:italic>atpE<\/jats:italic>\n                    , and\n                    <jats:italic>pepQ<\/jats:italic>\n                    for BDQ;\n                    <jats:italic>ddn<\/jats:italic>\n                    ,\n                    <jats:italic>fgd1<\/jats:italic>\n                    ,\n                    <jats:italic>fbiA<\/jats:italic>\n                    ,\n                    <jats:italic>fbiB<\/jats:italic>\n                    ,\n                    <jats:italic>fbiC<\/jats:italic>\n                    , and\n                    <jats:italic>fbiD<\/jats:italic>\n                    for DLM\/PTM). Here we investigated the genetic diversity of these loci across &gt;33,000\u00a0\n                    <jats:italic>M<\/jats:italic>\n                    <jats:italic>. tuberculosis<\/jats:italic>\n                    isolates. In addition, epistatic mutations in\n                    <jats:italic>mmpL5-mmpS5<\/jats:italic>\n                    as well as variants in\n                    <jats:italic>ndh<\/jats:italic>\n                    , implicated for DLM\/PTM resistance in\n                    <jats:italic>M. smegmatis<\/jats:italic>\n                    , were explored\n                    <jats:italic>.<\/jats:italic>\n                    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\n                    <jats:italic>mmpR5<\/jats:italic>\n                    ,\n                    <jats:italic>ddn<\/jats:italic>\n                    ) 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.\n                  <\/jats:p>","DOI":"10.1038\/s41598-021-98862-4","type":"journal-article","created":{"date-parts":[[2021,9,30]],"date-time":"2021-09-30T06:30:41Z","timestamp":1632983441000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":68,"title":["Genetic diversity of candidate loci linked to Mycobacterium tuberculosis resistance to bedaquiline, delamanid and pretomanid"],"prefix":"10.1038","volume":"11","author":[{"given":"Paula J.","family":"G\u00f3mez-Gonz\u00e1lez","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joao","family":"Perdigao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pedro","family":"Gomes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zully M.","family":"Puyen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Santos-Lazaro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gary","family":"Napier","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin L.","family":"Hibberd","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miguel","family":"Viveiros","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabel","family":"Portugal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susana","family":"Campino","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jody E.","family":"Phelan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taane G.","family":"Clark","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,9,30]]},"reference":[{"key":"98862_CR1","unstructured":"WHO. 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