{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,11]],"date-time":"2026-03-11T23:46:58Z","timestamp":1773272818138,"version":"3.50.1"},"update-to":[{"DOI":"10.1371\/journal.pcbi.1009855","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2022,2,23]],"date-time":"2022-02-23T00:00:00Z","timestamp":1645574400000}}],"reference-count":52,"publisher":"Public Library of Science (PLoS)","issue":"2","license":[{"start":{"date-parts":[[2022,2,10]],"date-time":"2022-02-10T00:00:00Z","timestamp":1644451200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"national institutes of health","doi-asserted-by":"publisher","award":["R01 GM078031"],"award-info":[{"award-number":["R01 GM078031"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01 GM118543"],"award-info":[{"award-number":["R01 GM118543"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R35 GM144042"],"award-info":[{"award-number":["R35 GM144042"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"national institutes of health","doi-asserted-by":"publisher","award":["R01 AI111957"],"award-info":[{"award-number":["R01 AI111957"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.ploscompbiol.org"],"crossmark-restriction":false},"short-container-title":["PLoS Comput Biol"],"abstract":"<jats:p>\n                    Antimicrobial resistance presents a significant health care crisis. The mutation F98Y in\n                    <jats:italic>Staphylococcus aureus<\/jats:italic>\n                    dihydrofolate reductase (SaDHFR) confers resistance to the clinically important antifolate trimethoprim (TMP). Propargyl-linked antifolates (PLAs), next generation DHFR inhibitors, are much more resilient than TMP against this F98Y variant, yet this F98Y substitution still reduces efficacy of these agents. Surprisingly, differences in the enantiomeric configuration at the stereogenic center of PLAs influence the isomeric state of the NADPH cofactor. To understand the molecular basis of F98Y-mediated resistance and how PLAs\u2019 inhibition drives NADPH isomeric states, we used protein design algorithms in the\n                    <jats:sc>osprey<\/jats:sc>\n                    protein design software suite to analyze a comprehensive suite of structural, biophysical, biochemical, and computational data. Here, we present a model showing how F98Y SaDHFR exploits a different anomeric configuration of NADPH to evade certain PLAs\u2019 inhibition, while other PLAs remain unaffected by this resistance mechanism.\n                  <\/jats:p>","DOI":"10.1371\/journal.pcbi.1009855","type":"journal-article","created":{"date-parts":[[2022,2,10]],"date-time":"2022-02-10T13:52:40Z","timestamp":1644501160000},"page":"e1009855","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":11,"title":["Chiral evasion and stereospecific antifolate resistance in Staphylococcus aureus"],"prefix":"10.1371","volume":"18","author":[{"given":"Siyu","family":"Wang","sequence":"first","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2064-405X","authenticated-orcid":true,"given":"Stephanie 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