{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T17:07:02Z","timestamp":1779210422009,"version":"3.51.4"},"reference-count":71,"publisher":"Microbiology Society","issue":"5","license":[{"start":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T00:00:00Z","timestamp":1779148800000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"ARC Linkage Infrastructure Grant","award":["LE230100090"],"award-info":[{"award-number":["LE230100090"]}]},{"name":"Australian Government Research Training Program Scholarship"},{"name":"ARC Future Fellowship","award":["FT220100152"],"award-info":[{"award-number":["FT220100152"]}]},{"name":"Mahidol University-MQ Research Seed Grant"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,5,19]]},"abstract":"<jats:p>\n                    Tuberculosis (TB), caused by\n                    <jats:italic>Mycobacterium tuberculosis<\/jats:italic>\n                    , is one of the world\u2019s deadliest diseases, currently responsible for ~1.5\u2009million deaths per year and rising. Recently, rifampicin-resistant\n                    <jats:italic>M. tuberculosis<\/jats:italic>\n                    was designated as a critical priority pathogen status by the World Health Organization. However, few controlled laboratory studies are available that systematically assess the molecular drivers of antibiotic resistance development in TB. In this study, we paired laboratory-directed evolution and population-level deep-sequencing approaches to map the evolutionary pathways taken by\n                    <jats:italic>M. tuberculosis<\/jats:italic>\n                    to develop resistance to first- and last-line therapies (rifampicin and linezolid) and then characterized\n                    <jats:italic>de novo<\/jats:italic>\n                    resistance mutation occurrence over time. We demonstrated that the majority of\n                    <jats:italic>M. tuberculosis<\/jats:italic>\n                    populations readily acquire mutations in genes commonly found in rifampicin- and linezolid-resistant clinical isolates (\n                    <jats:italic>rpoB<\/jats:italic>\n                    and\n                    <jats:italic>rplC<\/jats:italic>\n                    ). However, we also identified mutations in six genes, mostly present in subpopulations (17\u201341%) and not previously linked to rifampicin or linezolid resistance, including four associated with rifampicin resistance (\n                    <jats:italic>Rv0052<\/jats:italic>\n                    ,\n                    <jats:italic>ppsD<\/jats:italic>\n                    ,\n                    <jats:italic>ppsE<\/jats:italic>\n                    and\n                    <jats:italic>mptC<\/jats:italic>\n                    ) and two associated with linezolid resistance (\n                    <jats:italic>glpK<\/jats:italic>\n                    and\n                    <jats:italic>echA12<\/jats:italic>\n                    ). The\n                    <jats:italic>ppsD<\/jats:italic>\n                    ,\n                    <jats:italic>glpK<\/jats:italic>\n                    and\n                    <jats:italic>mptC<\/jats:italic>\n                    mutations were also identified in published individual sequencing reads of antibiotic-resistant clinical isolates. Further investigation of the identified resistance determinants\n                    <jats:italic>ppsD<\/jats:italic>\n                    \/\n                    <jats:italic>E<\/jats:italic>\n                    established that mutations in these genes appear to mediate resistance across multiple species, with an\n                    <jats:italic>Escherichia coli<\/jats:italic>\n                    mutant of the ortholog (\n                    <jats:italic>fabF<\/jats:italic>\n                    ), representing a shared domain featured in PpsD and PpsE, phenotypically displaying increased antibiotic tolerance to low-level rifampicin. This study highlights the power of using controlled laboratory studies to uncover minority variants in populations of\n                    <jats:italic>M. tuberculosis<\/jats:italic>\n                    . These outcomes will lead to improved diagnosis of antibiotic resistance emergence in TB, to optimize management and treatment of TB infections, and ultimately to minimize patient deaths.\n                  <\/jats:p>","DOI":"10.1099\/mgen.0.001723","type":"journal-article","created":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T16:16:34Z","timestamp":1779207394000},"source":"Crossref","is-referenced-by-count":0,"title":["Uncovering resistance pathways to first- and last-line antibiotics in Mycobacterium tuberculosis populations"],"prefix":"10.1099","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4882-516X","authenticated-orcid":false,"given":"Prapaporn","family":"Srilohasin","sequence":"first","affiliation":[{"name":"Department of Microbiology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, 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