{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T17:51:48Z","timestamp":1792000308163,"version":"4.4.0"},"update-to":[{"DOI":"10.1371\/journal.ppat.1012783","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2025,1,13]],"date-time":"2025-01-13T00:00:00Z","timestamp":1736726400000}}],"reference-count":68,"publisher":"Public Library of Science (PLoS)","issue":"12","license":[{"start":{"date-parts":[[2024,12,31]],"date-time":"2024-12-31T00:00:00Z","timestamp":1735603200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100018685","name":"Direcci\u00f3 General de Pol\u00edtica Universit\u00e0ria i Recerca, Govern Illes Balears","doi-asserted-by":"publisher","award":["RADIX17\/3-1\/2"],"award-info":[{"award-number":["RADIX17\/3-1\/2"]}],"id":[{"id":"10.13039\/100018685","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004587","name":"Instituto de Salud Carlos III","doi-asserted-by":"publisher","award":["CP20\/00138"],"award-info":[{"award-number":["CP20\/00138"]}],"id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100011033","name":"Agencia Estatal de Investigaci\u00f3n","doi-asserted-by":"publisher","award":["PROYECTOS DE I+D+i PID2020-112654RB-I00\/AEI\/10.13039\/501100011033"],"award-info":[{"award-number":["PROYECTOS DE I+D+i PID2020-112654RB-I00\/AEI\/10.13039\/501100011033"]}],"id":[{"id":"10.13039\/501100011033","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006492","name":"Division of Intramural Research, National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["R01AI136803"],"award-info":[{"award-number":["R01AI136803"]}],"id":[{"id":"10.13039\/100006492","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100008530","name":"European Regional Development Fund","doi-asserted-by":"publisher","award":["RD16\/0016"],"award-info":[{"award-number":["RD16\/0016"]}],"id":[{"id":"10.13039\/501100008530","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plospathogens.org"],"crossmark-restriction":false},"short-container-title":["PLoS Pathog"],"abstract":"<jats:p><jats:italic>Neisseria gonorrhoeae<\/jats:italic> exhibits alarming antibiotic resistance trends and poses a significant challenge in therapeutic management. This study aimed to explore the association of <jats:italic>penA<\/jats:italic> alleles with penicillin-binding protein (PBP) occupancy patterns and reduced outer membrane permeability, impacting susceptibility to last-line cephalosporins and potential \u03b2-lactam candidates. The whole genome sequence, the MICs and PBP IC<jats:sub>50<\/jats:sub>s were determined for 12 \u03b2-lactams and \u03b2-lactamase inhibitors in 8 clinical isolates with varying \u03b2-lactam sensitivity, 2 ATCC, and 3 WHO cephalosporin-resistant reference strains. The genetic analysis identified diverse determinants of \u03b2-lactam resistance including <jats:italic>penA<\/jats:italic>, <jats:italic>ponA<\/jats:italic>, <jats:italic>porB<\/jats:italic>, and <jats:italic>mtrR<\/jats:italic> alterations. Mosaic <jats:italic>penA<\/jats:italic> alleles were confirmed to be key determinants of cephalosporin resistance, with notable impacts on PBP2 IC<jats:sub>50<\/jats:sub> affinities (in the presence of all PBPs). Substitutions in positions V316 and A501 exhibited significant effects on \u03b2-lactam PBP2 occupancy and MICs. PBP1 inhibition showed marginal effect on \u03b2-lactam sensitivity and PBP3 acted as a sink target. Ertapenem and piperacillin emerged as potential therapies against cephalosporin-resistant <jats:italic>N<\/jats:italic>. <jats:italic>gonorrhoeae<\/jats:italic> strains, along with combination therapies involving tazobactam and\/or efflux inhibitors. The study determined the \u03b2-lactam PBP-binding affinities of last-line cephalosporins and alternative \u03b2-lactam candidates in strains carrying different <jats:italic>penA<\/jats:italic> alleles for the first time. These findings provide insights for developing new antimicrobial agents and enhancers against emerging resistant strains. Further research is warranted to optimize therapeutic interventions for cephalosporin-resistant <jats:italic>N<\/jats:italic>. <jats:italic>gonorrhoeae<\/jats:italic> infections.<\/jats:p>","DOI":"10.1371\/journal.ppat.1012783","type":"journal-article","created":{"date-parts":[[2024,12,31]],"date-time":"2024-12-31T19:07:32Z","timestamp":1735672052000},"page":"e1012783","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":5,"title":["Differential contribution of PBP occupancy and efflux on the effectiveness of \u03b2-lactams at their target site in clinical isolates of Neisseria gonorrhoeae"],"prefix":"10.1371","volume":"20","author":[{"given":"Silvia","family":"L\u00f3pez-Arg\u00fcello","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eva","family":"Alcoceba","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paula","family":"Ord\u00f3\u00f1ez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Biel","family":"Taltavull","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriel","family":"Cabot","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Antonia","family":"Gomis-Font","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonio","family":"Oliver","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bartolome","family":"Moya","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2024,12,31]]},"reference":[{"issue":"6","key":"ppat.1012783.ref001","doi-asserted-by":"crossref","first-page":"1523","DOI":"10.1093\/jac\/dkab037","article-title":"Neisseria gonorrhoeaeNeisseria gonorrhoeae antimicrobial resistance in Spain: a prospective multicentre study","volume":"76","author":"P Salmer\u00f3n","year":"2021","journal-title":"J Antimicrob Chemother"},{"key":"ppat.1012783.ref002","author":"ECDC","year":"2023","journal-title":"Sexually transmitted infections in 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characterization of the first strain with high-level resistance to ceftriaxone","volume":"55","author":"M Ohnishi","year":"2011","journal-title":"Antimicrob Agents Chemother"},{"issue":"3","key":"ppat.1012783.ref006","doi-asserted-by":"crossref","first-page":"1273","DOI":"10.1128\/AAC.05760-11","article-title":"High-level cefixime- and ceftriaxone-resistant Neisseria gonorrhoeae in France: novel penA mosaic allele in a successful international clone causes treatment failure","volume":"56","author":"M Unemo","year":"2012","journal-title":"Antimicrob Agents Chemother"},{"issue":"19","key":"ppat.1012783.ref007","doi-asserted-by":"crossref","first-page":"1850","DOI":"10.1056\/NEJMc1408109","article-title":"A new multidrug-resistant strain of Neisseria gonorrhoeae in Australia","volume":"371","author":"MM Lahra","year":"2014","journal-title":"N Engl J Med"},{"issue":"46","key":"ppat.1012783.ref008","first-page":"2200803","article-title":"Detection of 10 cases of 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Penicillin-Binding Protein 2 on Cephalosporin and Carbapenem Susceptibilities in Neisseria gonorrhoeae","volume":"59","author":"A Bharat","year":"2015","journal-title":"Antimicrob Agents Chemother"},{"issue":"9","key":"ppat.1012783.ref026","doi-asserted-by":"crossref","first-page":"1549","DOI":"10.1007\/s10096-016-2696-7","article-title":"Neisseria gonorrhoeae antimicrobial susceptibility in Barcelona: penA, ponA, mtrR, and porB mutations and NG-MAST sequence types associated with decreased susceptibility to cephalosporins","volume":"35","author":"J Serra-Pladevall","year":"2016","journal-title":"Eur J Clin Microbiol Infect Dis"},{"issue":"3","key":"ppat.1012783.ref027","doi-asserted-by":"crossref","first-page":"769","DOI":"10.1128\/AAC.46.3.769-777.2002","article-title":"Mutations in ponA, the gene encoding penicillin-binding protein 1, and a novel locus, penC, are required for high-level chromosomally mediated penicillin resistance in Neisseria gonorrhoeae","volume":"46","author":"PA 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penicillin-binding proteins in penicillin-resistant strains of Neisseria gonorrhoeae","volume":"332","author":"BG Spratt","year":"1988","journal-title":"Nature"},{"issue":"1","key":"ppat.1012783.ref034","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1128\/AAC.20.1.109","article-title":"Competition of beta-lactam antibiotics for the penicillin-binding proteins of Neisseria gonorrhoeae","volume":"20","author":"TJ Dougherty","year":"1981","journal-title":"Antimicrob Agents Chemother"},{"issue":"2","key":"ppat.1012783.ref035","doi-asserted-by":"crossref","first-page":"1202","DOI":"10.1074\/jbc.M805761200","article-title":"Crystal structures of penicillin-binding protein 2 from penicillin-susceptible and -resistant strains of Neisseria gonorrhoeae reveal an unexpectedly subtle mechanism for antibiotic resistance","volume":"284","author":"AJ Powell","year":"2009","journal-title":"J Biol 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penicillin-binding protein 2.","volume":"7","author":"A Fedarovich","year":"2012","journal-title":"PLoS One"},{"issue":"3","key":"ppat.1012783.ref042","doi-asserted-by":"crossref","first-page":"1060","DOI":"10.1128\/AAC.01010-09","article-title":"Spread of a chromosomal cefixime-resistant penA gene among different Neisseria gonorrhoeae lineages","volume":"54","author":"M Ohnishi","year":"2010","journal-title":"Antimicrob Agents Chemother"},{"issue":"7","key":"ppat.1012783.ref043","doi-asserted-by":"crossref","first-page":"3603","DOI":"10.1128\/AAC.00326-12","article-title":"In vitro activity of ertapenem versus ceftriaxone against Neisseria gonorrhoeae isolates with highly diverse ceftriaxone MIC values and effects of ceftriaxone resistance determinants: ertapenem for treatment of gonorrhea?","volume":"56","author":"M Unemo","year":"2012","journal-title":"Antimicrob Agents 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penA gene from Neisseria gonorrhoeae strain H041","volume":"57","author":"J Tomberg","year":"2013","journal-title":"Antimicrob Agents Chemother"},{"issue":"9","key":"ppat.1012783.ref047","doi-asserted-by":"crossref","first-page":"3744","DOI":"10.1128\/AAC.00304-09","article-title":"Genetics of chromosomally mediated intermediate resistance to ceftriaxone and cefixime in Neisseria gonorrhoeae","volume":"53","author":"S Zhao","year":"2009","journal-title":"Antimicrob Agents Chemother"},{"issue":"4","key":"ppat.1012783.ref048","doi-asserted-by":"crossref","first-page":"907","DOI":"10.1093\/jac\/dkz530","article-title":"Emergence of ceftriaxone-resistant Neisseria gonorrhoeae strains harbouring a novel mosaic penA gene in China","volume":"75","author":"L Xiu","year":"2020","journal-title":"J Antimicrob Chemother"},{"issue":"3","key":"ppat.1012783.ref049","doi-asserted-by":"crossref","DOI":"10.1128\/AAC.02069-17","article-title":"Neisseria cinerea with High Ceftriaxone MIC Is a Source of Ceftriaxone and Cefixime Resistance-Mediating","volume":"62","author":"G Igawa","year":"2018","journal-title":"Antimicrob Agents Chemother"},{"issue":"9","key":"ppat.1012783.ref050","doi-asserted-by":"crossref","first-page":"3933","DOI":"10.1128\/AAC.00296-10","article-title":"Affinity of the new cephalosporin CXA-101 to penicillin-binding proteins of Pseudomonas aeruginosa","volume":"54","author":"B Moya","year":"2010","journal-title":"Antimicrob Agents Chemother"},{"issue":"3","key":"ppat.1012783.ref051","doi-asserted-by":"crossref","first-page":"1213","DOI":"10.1128\/AAC.01104-09","article-title":"Activity of a new cephalosporin, CXA-101 (FR264205), against beta-lactam-resistant Pseudomonas aeruginosa mutants selected in vitro and after antipseudomonal treatment of intensive care unit patients.","volume":"54","author":"B Moya","year":"2010","journal-title":"Antimicrob Agents 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