{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T17:50:40Z","timestamp":1792000240515,"version":"4.4.0"},"reference-count":38,"publisher":"American Society for Microbiology","issue":"7","license":[{"start":{"date-parts":[[2013,7,1]],"date-time":"2013-07-01T00:00:00Z","timestamp":1372636800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Antimicrob Agents Chemother"],"published-print":{"date-parts":[[2013,7]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    The recent identification of a high-level-ceftriaxone-resistant (MIC = 2 to 4 \u03bcg\/ml) isolate of\n                    <jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">Neisseria gonorrhoeae<\/jats:named-content>\n                    from Japan (H041) portends the loss of ceftriaxone as an effective treatment for gonococcal infections. This is of grave concern because ceftriaxone is the last remaining option for first-line empirical antimicrobial monotherapy. The\n                    <jats:italic>penA<\/jats:italic>\n                    gene from H041 (\n                    <jats:italic>penA41<\/jats:italic>\n                    ) is a mosaic\n                    <jats:italic>penA<\/jats:italic>\n                    allele similar to mosaic alleles conferring intermediate-level cephalosporin resistance (Ceph\n                    <jats:sup>i<\/jats:sup>\n                    ) worldwide but has 13 additional mutations compared to the mosaic\n                    <jats:italic>penA<\/jats:italic>\n                    gene from the previously studied Ceph\n                    <jats:sup>i<\/jats:sup>\n                    strain 35\/02 (\n                    <jats:italic>penA35<\/jats:italic>\n                    ). When transformed into the wild-type strain FA19, the\n                    <jats:italic>penA41<\/jats:italic>\n                    allele confers 300- and 570-fold increases in the MICs for ceftriaxone and cefixime, respectively. In order to understand the mechanisms involved in high-level ceftriaxone resistance and to improve surveillance and epidemiology during the potential emergence of ceftriaxone resistance, we sought to identify the minimum number of amino acid alterations above those in\n                    <jats:italic>penA35<\/jats:italic>\n                    that confer high-level resistance to ceftriaxone. Using restriction fragment exchange and site-directed mutagenesis, we identified three mutations, A311V, T316P, and T483S, that, when incorporated into the mosaic\n                    <jats:italic>penA35<\/jats:italic>\n                    allele, confer essentially all of the increased resistance of\n                    <jats:italic>penA41<\/jats:italic>\n                    . A311V and T316P are close to the active-site nucleophile Ser310 that forms the acyl-enzyme complex, while Thr483 is predicted to interact with the carboxylate of the \u03b2-lactam antibiotic. These three mutations have thus far been described only for\n                    <jats:italic>penA41<\/jats:italic>\n                    , but dissemination of these mutations in other mosaic alleles would spell the end of ceftriaxone as an effective treatment for gonococcal infections.\n                  <\/jats:p>","DOI":"10.1128\/aac.00093-13","type":"journal-article","created":{"date-parts":[[2013,4,15]],"date-time":"2013-04-15T21:48:44Z","timestamp":1366062524000},"page":"3029-3036","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":75,"title":["Identification of Amino Acids Conferring High-Level Resistance to Expanded-Spectrum Cephalosporins in the\n                    <i>penA<\/i>\n                    Gene from Neisseria gonorrhoeae Strain H041"],"prefix":"10.1128","volume":"57","author":[{"given":"Joshua","family":"Tomberg","sequence":"first","affiliation":[{"name":"Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Magnus","family":"Unemo","sequence":"additional","affiliation":[{"name":"WHO Collaborating Centre for Gonorrhoea and Other STIs, Department of Laboratory Medicine, Microbiology, \u00d6rebro University Hospital, \u00d6rebro, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Makoto","family":"Ohnishi","sequence":"additional","affiliation":[{"name":"National Institute of Infectious Diseases, Tokyo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher","family":"Davies","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, South Carolina, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert A.","family":"Nicholas","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA"},{"name":"Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","unstructured":"World Health Organization. 2008. Global incidence and prevalence of selected curable sexually transmitted infections\u20142008. World Health Organization Geneva Switzerland. http:\/\/www.who.int\/reproductivehealth\/publications\/rtis\/2008_STI_estimates.pdf."},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1749-6632.2011.06215.x"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.2217\/fmb.12.117"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(76)92466-1"},{"key":"e_1_3_2_6_2","first-page":"332","article-title":"Update to CDC's sexually transmitted diseases treatment guidelines, 2006: fluoroquinolones no longer recommended for treatment of gonococcal infections","volume":"56","author":"CDC","year":"2007","unstructured":"CDC. 2007. Update to CDC's sexually transmitted diseases treatment guidelines, 2006: fluoroquinolones no longer recommended for treatment of gonococcal infections. MMWR Morb. Mortal. Wkly. 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