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Based on previous work from our lab and others, we identified a minimal set of 10 mutations that, when introduced into the \u03b2-lactam antibiotic-susceptible\n                    <jats:italic>penA<\/jats:italic>\n                    allele from FA19 (\n                    <jats:italic>penA19<\/jats:italic>\n                    ), confers two-thirds of the ceftriaxone and cefixime resistance compared to the\n                    <jats:italic>penA41<\/jats:italic>\n                    allele. Three mutations (A311V, I312M, and V316P) are in the\n                    <jats:italic>\u03b1<\/jats:italic>\n                    2 helix of PBP2 containing the catalytic serine (Ser310), two (F504L and N512Y) are in the\n                    <jats:italic>\u03b2<\/jats:italic>\n                    3-\n                    <jats:italic>\u03b2<\/jats:italic>\n                    4 loop that is important in binding and acylation, and one (G545S) interacts with conserved amino acids in the active site. The seventh mutation, T483S, confers substantial resistance to ceftriaxone within the minimal mutant set but requires the presence of three epistatic mutations located on the other side of the protein that do not alter resistance on their own yet are necessary to retain essential function. These epistatic mutations change the backbone dihedral angles at position-447, which may increase flexibility of the enzyme and help maintain enzymatic function. Our results highlight the complex balance necessary for evolving cephalosporin resistance in PBP2 while also retaining sufficient transpeptidase function to support growth.\n                  <\/jats:p>","DOI":"10.1371\/journal.ppat.1013721","type":"journal-article","created":{"date-parts":[[2026,3,17]],"date-time":"2026-03-17T17:37:46Z","timestamp":1773769066000},"page":"e1013721","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":1,"title":["Antibiotic-resistance mutations in penicillin-binding protein 2 from the ceftriaxone-resistant Neisseria gonorrhoeae strain H041 strike a delicate balance between increasing resistance and maintaining transpeptidase activity"],"prefix":"10.1371","volume":"22","author":[{"given":"Marissa M.","family":"Bivins","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joshua","family":"Tomberg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Madeleine","family":"Bagshaw","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Avinash","family":"Singh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandeepchowdary","family":"Bala","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher","family":"Davies","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2507-8974","authenticated-orcid":true,"given":"Robert A.","family":"Nicholas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2026,3,17]]},"reference":[{"issue":"1","key":"ppat.1013721.ref001","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1038\/s41572-019-0128-6","article-title":"Gonorrhoea","volume":"5","author":"M Unemo","year":"2019","journal-title":"Nat Rev Dis Primers"},{"key":"ppat.1013721.ref002","unstructured":"CDC. 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