{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,12]],"date-time":"2026-09-12T14:30:16Z","timestamp":1789223416363,"version":"build-2803163510"},"reference-count":43,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,4,14]],"date-time":"2022-04-14T00:00:00Z","timestamp":1649894400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p>Novel antimicrobials for effective treatment of uncomplicated gonorrhea are essential, and the first-in-class, oral spiropyrimidinetrione DNA gyrase B inhibitor zoliflodacin appears promising. Using our newly developed Hollow Fiber Infection Model (HFIM), the pharmacodynamics of zoliflodacin was examined. A clinical zoliflodacin-susceptible <jats:italic>N. gonorrhoeae<\/jats:italic> strain, SE600\/18 (harbouring a GyrB S467N amino acid substitution; MIC = 0.25\u00a0mg\/L), and SE600\/18-D429N (zoliflodacin-resistant mutant with a second GyrB substitution, D429N, selected in the HFIM experiments; zoliflodacin MIC = 2\u00a0mg\/L), were examined. Dose-range experiments, simulating zoliflodacin single oral dose regimens of 0.5, 1, 2, 3, and 4\u00a0g, were performed for SE600\/18. For SE600\/18-D429N, dose-range experiments, simulating zoliflodacin single oral 2, 3, 4, and 6\u00a0g doses, and zoliflodacin oral dose-fractionation experiments with 4, 6, and 8\u00a0g administered as q12\u00a0h were performed. Both strains grew well in the untreated HFIM growth control arms and mostly maintained growth at 10<jats:sup>10<\/jats:sup>\u201310<jats:sup>11<\/jats:sup>\u00a0CFU\/ml for 7\u00a0days. Zoliflodacin 3 and 4\u00a0g single dose oral regimens successfully eradicated SE600\/18 and no growth was recovered during the 7-days experiments. However, the single oral 0.5, 1, and 2\u00a0g doses failed to eradicate SE600\/18, and zoliflodacin-resistant populations with a GyrB D429N substitution were selected with all these doses. The zoliflodacin-resistant SE600\/18-D429N mutant was not eradicated with any examined treatment regimen. However, this <jats:italic>in vitro<\/jats:italic>-selected zoliflodacin-resistant mutant was substantially less fit compared to the zoliflodacin-susceptible SE600\/18 parent strain. In conclusion, the rare clinical gonococcal strains with GyrB S467N substitution are predisposed to develop zoliflodacin resistance and may require treatment with zoliflodacin \u22653\u00a0g. Future development may need to consider the inclusion of diagnostics directed at identifying strains resistant or predisposed to resistance development at a population level and to strengthen surveillance (phenotypically and genetically), and possibly also at the patient level to guide treatment.<\/jats:p>","DOI":"10.3389\/fphar.2022.874176","type":"journal-article","created":{"date-parts":[[2022,4,14]],"date-time":"2022-04-14T06:51:31Z","timestamp":1649919091000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":29,"title":["Pharmacodynamic Evaluation of Zoliflodacin Treatment of Neisseria gonorrhoeae Strains With Amino Acid Substitutions in the Zoliflodacin Target GyrB Using a Dynamic Hollow Fiber Infection Model"],"prefix":"10.3389","volume":"13","author":[{"given":"Susanne","family":"Jacobsson","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Golparian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joakim","family":"Oxelbark","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francois","family":"Franceschi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Brown","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arnold","family":"Louie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"George","family":"Drusano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Magnus","family":"Unemo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,4,14]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"2847","DOI":"10.1093\/jac\/dkab262","article-title":"Using a Public Database of Neisseria Gonorrhoeae Genomes to Detect Mutations Associated with Zoliflodacin Resistance","volume":"76","author":"Adamson","year":"2021","journal-title":"J. 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