{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T13:52:37Z","timestamp":1791381157890,"version":"4.3.3"},"reference-count":31,"publisher":"American Society for Microbiology","issue":"10","license":[{"start":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T00:00:00Z","timestamp":1791331200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T00:00:00Z","timestamp":1791331200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["AI132606"],"award-info":[{"award-number":["AI132606"]}],"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":["AI153521"],"award-info":[{"award-number":["AI153521"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Antimicrob Agents Chemother"],"published-print":{"date-parts":[[2026,10,7]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title\/>\n                    <jats:p>\n                      <jats:italic toggle=\"yes\">Neisseria gonorrhoeae<\/jats:italic>\n                      is a major public health concern due to its high global prevalence and rapid evolution of antibiotic resistance. A first-in-class topoisomerase inhibitor, zoliflodacin (a spiropyrimidinetrione), recently received FDA approval for treatment of gonorrhea, but its potential for cross-resistance with another topoisomerase inhibitor, the fluoroquinolone antibiotic ciprofloxacin, remains poorly understood. Here, we investigated how genetic diversity in the fluoroquinolone target\n                      <jats:italic toggle=\"yes\">gyrA<\/jats:italic>\n                      influences the resistance and fitness effects of the zoliflodacin resistance mutation\n                      <jats:italic toggle=\"yes\">gyrB<\/jats:italic>\n                      <jats:sup>D429N<\/jats:sup>\n                      . We constructed an isogenic panel of\n                      <jats:italic toggle=\"yes\">N. gonorrhoeae<\/jats:italic>\n                      to determine how the resistance and fitness effects of the\n                      <jats:italic toggle=\"yes\">gyrB<\/jats:italic>\n                      <jats:sup>D429N<\/jats:sup>\n                      mutation are modulated by the most common ciprofloxacin resistance-associated variants in\n                      <jats:italic toggle=\"yes\">gyrA<\/jats:italic>\n                      . In the presence of\n                      <jats:italic toggle=\"yes\">gyrB<\/jats:italic>\n                      <jats:sup>D429N<\/jats:sup>\n                      , the zoliflodacin minimum inhibitory concentration (MIC) was two- to fourfold higher in strains that also contained ciprofloxacin resistance-associated\n                      <jats:italic toggle=\"yes\">gyrA<\/jats:italic>\n                      alleles, and the\n                      <jats:italic toggle=\"yes\">gyrB<\/jats:italic>\n                      <jats:sup>D429N<\/jats:sup>\n                      mutation reciprocally increased ciprofloxacin MICs of these strains three- to sixfold. The fitness cost of the\n                      <jats:italic toggle=\"yes\">gyrB<\/jats:italic>\n                      <jats:sup>D429N<\/jats:sup>\n                      mutation varied from modest to severe across\n                      <jats:italic toggle=\"yes\">gyrA<\/jats:italic>\n                      backgrounds, with the largest cost in ciprofloxacin-resistant\n                      <jats:italic toggle=\"yes\">gyrA<\/jats:italic>\n                      <jats:sup>91F\/95G<\/jats:sup>\n                      and\n                      <jats:italic toggle=\"yes\">gyrA<\/jats:italic>\n                      <jats:sup>91F\/95N<\/jats:sup>\n                      backgrounds and comparatively minimal cost in the ciprofloxacin-resistant\n                      <jats:italic toggle=\"yes\">gyrA<\/jats:italic>\n                      <jats:sup>91F\/95A<\/jats:sup>\n                      background. These results demonstrate the capacity for epistatic interactions among resistance-associated\n                      <jats:italic toggle=\"yes\">gyrA<\/jats:italic>\n                      and\n                      <jats:italic toggle=\"yes\">gyrB<\/jats:italic>\n                      mutations, underscoring the need for genomic surveillance to monitor high-risk combinations of resistance determinants as new therapies are deployed.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1128\/aac.00766-26","type":"journal-article","created":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T14:17:07Z","timestamp":1787149027000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":1,"title":["Fluoroquinolone resistance-conferring\n                    <i>gyrA<\/i>\n                    variants alter the fitness cost and potentiate the resistance of the zoliflodacin resistance mutation\n                    <i>gyrB<\/i>\n                    <sup>D429N<\/sup>\n                    in\n                    <i>Neisseria gonorrhoeae<\/i>"],"prefix":"10.1128","volume":"70","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2208-9945","authenticated-orcid":true,"given":"Aditi","family":"Mukherjee","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/044r51149","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Immunology and Infectious Diseases, Harvard T. H. Chan School of Public Health","place":["Boston, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sofia O. P.","family":"Blomqvist","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/044r51149","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Immunology and Infectious Diseases, Harvard T. H. Chan School of Public Health","place":["Boston, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Helekal","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/044r51149","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Immunology and Infectious Diseases, Harvard T. H. Chan School of Public Health","place":["Boston, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel H. F.","family":"Rubin","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/044r51149","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Immunology and Infectious Diseases, Harvard T. H. Chan School of Public Health","place":["Boston, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5908-9765","authenticated-orcid":true,"given":"Bailey","family":"Bowcutt","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/044r51149","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Immunology and Infectious Diseases, Harvard T. H. Chan School of Public Health","place":["Boston, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7849-8078","authenticated-orcid":true,"given":"Samantha G.","family":"Palace","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/044r51149","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Immunology and Infectious Diseases, Harvard T. H. Chan School of Public Health","place":["Boston, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5646-1314","authenticated-orcid":true,"given":"Yonatan H.","family":"Grad","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/044r51149","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Immunology and Infectious Diseases, Harvard T. H. Chan School of Public Health","place":["Boston, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(25)00118-5"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1128\/CMR.00010-14"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/ciac043"},{"key":"e_1_3_4_5_2","unstructured":"U.S. Food and Drug Administration. 2025. FDA approves two oral therapies to treat gonorrhea. Available from: https:\/\/www.fda.gov\/news-events\/press-announcements\/fda-approves-two-oral-therapies-treat-gonorrhea"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2958.1994.tb01297.x"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.15585\/mmwr.mm7312a2"},{"key":"e_1_3_4_8_2","volume-title":"Sexually transmitted disease surveillance January-July 2024: Gonococcal Isolate Surveillance Project national profile","author":"Centers for Disease Control and Prevention","year":"2025","unstructured":"Centers for Disease Control and Prevention. 2025 Sexually transmitted disease surveillance January-July 2024: Gonococcal Isolate Surveillance Project national profile. 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