{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T13:01:03Z","timestamp":1792155663956,"version":"4.4.0"},"reference-count":29,"publisher":"Public Library of Science (PLoS)","issue":"12","license":[{"start":{"date-parts":[[2025,12,4]],"date-time":"2025-12-04T00:00:00Z","timestamp":1764806400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS One"],"abstract":"<jats:p>\n                    Mutations in\n                    <jats:italic>rpoB<\/jats:italic>\n                    , a gene that encodes the bacterial RNA polymerase (RNAP) beta-subunit, can cause high-level resistance to rifampicin. Approximately 95% of rifampicin-resistant\n                    <jats:italic>Mycobacterium tuberculosis<\/jats:italic>\n                    clinical isolates harbour mutations in an 81-base pair\n                    <jats:italic>rpoB<\/jats:italic>\n                    region referred to as the rifampicin-resistance-determining region (\n                    <jats:italic>rpoB<\/jats:italic>\n                    \/RRDR). Also, rifampicin-resistant\n                    <jats:italic>M. tuberculosis<\/jats:italic>\n                    clinical isolates carry multiple mutations in RNAP genes (i.e.,\n                    <jats:italic>rpoA, rpoB<\/jats:italic>\n                    ,\n                    <jats:italic>rpoC, rpoD<\/jats:italic>\n                    ), particularly\n                    <jats:italic>rpoA<\/jats:italic>\n                    and\n                    <jats:italic>rpoC,<\/jats:italic>\n                    which encode the alpha- (\u03b1\n                    <jats:sub>2<\/jats:sub>\n                    ) and beta\u2032- (\u03b2\u2032) subunits, respectively. Such secondary mutations offset the fitness cost associated with acquisition of rifampicin-resistance mutations in\n                    <jats:italic>M. tuberculosis<\/jats:italic>\n                    , resulting in resistant strains that are as fit as the wild-type drug-susceptible strains. To analyse the patterns of compensatory mutations in RNAP encoding genes of rifampicin-resistant\n                    <jats:italic>M. tuberculosis<\/jats:italic>\n                    clinical isolates in Uganda, whole genome sequencing and Sanger DNA sequencing were performed on 52\n                    <jats:italic>M. tuberculosis<\/jats:italic>\n                    clinical isolates \u2013 20 drug-susceptible and 32 multidrug resistant (MDR). A total of 24 (75%) MDR-TB isolates had high-level rifampicin-resistance-conferring mutations in\n                    <jats:italic>rpoB<\/jats:italic>\n                    \/RRDR, i.e., Ser531Leu (31%); His526Asp (6%); His526Leu (3%); His526Tyr (3%); His526Arg (3%); His526Gly (3%); Asp516Tyr (13%); Asp516Val (6%); Glu513Lys (3%); Leu511Pro (3%); Leu492Leu (3%); Gln490Arg (3%). Further, two putative compensatory mutations (Gln490Arg &amp; Lys1025Glu) outside the RRDR and not resistance-conferring were found in\n                    <jats:italic>rpoB<\/jats:italic>\n                    . Altogether, 15 (63%, 15\/24) MDR-TB isolates with\n                    <jats:italic>rpoB<\/jats:italic>\n                    \/RRDR resistance-conferring mutations had non-synonymous mutations in\n                    <jats:italic>rpoC<\/jats:italic>\n                    of the following patterns Leu39Phe (3%); Tyr61His (3%); Asp271Gly (3%); Ser377Ala (3%); Pro481Thr (3%); Val483Ala (6%); Leu516Pro (3%); Ala521Asp (3%); Gly594Glu (13%); Asn698Ser (3%); Leu823Pro (3%). In conclusion, putative compensatory mutations are prevalent in rifampicin-resistant\n                    <jats:italic>M. tuberculosis<\/jats:italic>\n                    clinical isolates in Uganda, with\n                    <jats:italic>rpoC<\/jats:italic>\n                    \/Gly594Glu and\n                    <jats:italic>rpoC<\/jats:italic>\n                    \/Val483Ala as the most frequent. Further studies will determine their association with strain genetic background, fitness and transmission in an endemic setting with a high burden of HIV-TB coinfection.\n                  <\/jats:p>","DOI":"10.1371\/journal.pone.0328957","type":"journal-article","created":{"date-parts":[[2025,12,4]],"date-time":"2025-12-04T18:58:07Z","timestamp":1764874687000},"page":"e0328957","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":2,"title":["Patterns of compensatory mutations in rpoA\/B\/C genes of multidrug resistant M. tuberculosis in Uganda"],"prefix":"10.1371","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8075-3069","authenticated-orcid":true,"given":"David 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