{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,23]],"date-time":"2026-03-23T23:39:56Z","timestamp":1774309196011,"version":"3.50.1"},"update-to":[{"DOI":"10.1371\/journal.pgen.1012011","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2026,1,12]],"date-time":"2026-01-12T00:00:00Z","timestamp":1768176000000}}],"reference-count":72,"publisher":"Public Library of Science (PLoS)","issue":"12","license":[{"start":{"date-parts":[[2025,12,31]],"date-time":"2025-12-31T00:00:00Z","timestamp":1767139200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/publicdomain\/zero\/1.0\/"}],"funder":[{"name":"Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research"}],"content-domain":{"domain":["www.plosgenetics.org"],"crossmark-restriction":false},"short-container-title":["PLoS Genet"],"abstract":"<jats:p>\n                    Gene amplification is thought to be common in bacterial populations, providing a rapid and reversible mode of adaptation to diverse stresses, including the acquisition of antibiotic resistance. We previously showed that the opportunistic pathogen\n                    <jats:italic>Staphylococcus aureus<\/jats:italic>\n                    evolves resistance to the dual-targeting fluoroquinolone delafloxacin (DLX) that inhibits both the DNA gyrase and DNA topoisomerase IV via amplification of an efflux pump encoding gene\n                    <jats:italic>sdrM<\/jats:italic>\n                    . However, the pathways that control gene amplification, and consequently adaptive trajectories, remain understudied, especially in gram-positive bacteria like\n                    <jats:italic>S. aureus<\/jats:italic>\n                    . Here, we show that specific DNA repair and chromosomal separation proteins alter the frequency of gene amplification and selection of amplified regions in\n                    <jats:italic>S. aureus<\/jats:italic>\n                    . Through a screen of 40 mutants deficient in various DNA processes, we determined that while\n                    <jats:italic>sdrM<\/jats:italic>\n                    amplification was still the almost universal path to DLX resistance, other mutations that increased\n                    <jats:italic>sdrM<\/jats:italic>\n                    expression reduced the selection frequency of\n                    <jats:italic>sdrM<\/jats:italic>\n                    amplification, demonstrating the critical role of\n                    <jats:italic>sdrM<\/jats:italic>\n                    in DLX resistance. We found that similar to other bacteria, both\n                    <jats:italic>sdrM<\/jats:italic>\n                    amplification and loss of amplified gene copies required a functional RecA recombinase, but multiple other mutants in pathways required for amplification in other species still exhibited frequent\n                    <jats:italic>sdrM<\/jats:italic>\n                    amplification, suggesting that\n                    <jats:italic>S. aureus<\/jats:italic>\n                    may have alternate routes of gene amplification. Finally, loss of function mutants of the tyrosine recombinase XerC, that is known to play a role in chromosomal separation, were deficient for\n                    <jats:italic>sdrM<\/jats:italic>\n                    amplification, indicating that XerC is a novel modulator of gene amplification, or the maintenance or selection of amplified gene copies. Thus, our work sheds light on genetic factors that alter gene amplification-mediated evolutionary trajectories to antibiotic resistance in\n                    <jats:italic>S. aureus<\/jats:italic>\n                    and can potentially unlock mechanisms by which such evolution of resistance can be inhibited.\n                  <\/jats:p>","DOI":"10.1371\/journal.pgen.1012011","type":"journal-article","created":{"date-parts":[[2025,12,31]],"date-time":"2025-12-31T18:50:11Z","timestamp":1767207011000},"page":"e1012011","update-policy":"https:\/\/doi.org\/10.1371\/journal.pgen.corrections_policy","source":"Crossref","is-referenced-by-count":1,"title":["Modulators of gene amplification alter evolution of antibiotic resistance in Staphylococcus aureus"],"prefix":"10.1371","volume":"21","author":[{"given":"Kalinga Pavan T.","family":"Silva","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2319-830X","authenticated-orcid":true,"given":"Anthony M.","family":"Martini","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1231-670X","authenticated-orcid":true,"given":"Anupama","family":"Khare","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2025,12,31]]},"reference":[{"issue":"12","key":"pgen.1012011.ref001","doi-asserted-by":"crossref","DOI":"10.15252\/embr.202051034","article-title":"Antibiotic resistance and persistence-Implications for human health and treatment perspectives","volume":"21","author":"M Huemer","year":"2020","journal-title":"EMBO 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