{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T07:09:45Z","timestamp":1791356985815,"version":"4.3.1"},"reference-count":78,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2023,1,13]],"date-time":"2023-01-13T00:00:00Z","timestamp":1673568000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Since 2000, some thirteen quinolones and fluoroquinolones have been developed and have come to market. The quinolones, one of the most successful classes of antibacterial drugs, stabilize DNA cleavage complexes with DNA gyrase and topoisomerase IV (topo IV), the two bacterial type IIA topoisomerases. The dual targeting of gyrase and topo IV helps decrease the likelihood of resistance developing. Here, we report on a 2.8 \u00c5 X-ray crystal structure, which shows that zoliflodacin, a spiropyrimidinetrione antibiotic, binds in the same DNA cleavage site(s) as quinolones, sterically blocking DNA religation. The structure shows that zoliflodacin interacts with highly conserved residues on GyrB (and does not use the quinolone water\u2013metal ion bridge to GyrA), suggesting it may be more difficult for bacteria to develop target mediated resistance. We show that zoliflodacin has an MIC of 4 \u00b5g\/mL against Acinetobacter baumannii (A. baumannii), an improvement of four-fold over its progenitor QPT-1. The current phase III clinical trial of zoliflodacin for gonorrhea is due to be read out in 2023. Zoliflodacin, together with the unrelated novel bacterial topoisomerase inhibitor gepotidacin, is likely to become the first entirely novel chemical entities approved against Gram-negative bacteria in the 21st century. Zoliflodacin may also become the progenitor of a new safer class of antibacterial drugs against other problematic Gram-negative bacteria.<\/jats:p>","DOI":"10.3390\/ijms24021634","type":"journal-article","created":{"date-parts":[[2023,1,16]],"date-time":"2023-01-16T02:04:45Z","timestamp":1673834685000},"page":"1634","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":32,"title":["A 2.8 \u00c5 Structure of Zoliflodacin in a DNA Cleavage Complex with Staphylococcus aureus DNA Gyrase"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7349-1486","authenticated-orcid":false,"given":"Harry","family":"Morgan","sequence":"first","affiliation":[{"name":"Medicines Discovery Institute, Cardiff University, Cardiff CF10 3AT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Magdalena","family":"Lipka-Lloyd","sequence":"additional","affiliation":[{"name":"Medicines Discovery Institute, Cardiff University, Cardiff CF10 3AT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna J.","family":"Warren","sequence":"additional","affiliation":[{"name":"Diamond Light Source, Harwell Science and Innovation Campus, Didcot OX11 0DE, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naomi","family":"Hughes","sequence":"additional","affiliation":[{"name":"Cardiff School of Biosciences, Cardiff University, Cardiff CF10 3AX, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Holmes","sequence":"additional","affiliation":[{"name":"Inspiralis Limited, Norwich Research Park Innovation Centre, Norwich NR4 7GJ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicolas P.","family":"Burton","sequence":"additional","affiliation":[{"name":"Inspiralis Limited, Norwich Research Park Innovation Centre, Norwich NR4 7GJ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eshwar","family":"Mahenthiralingam","sequence":"additional","affiliation":[{"name":"Cardiff School of Biosciences, Cardiff University, Cardiff CF10 3AX, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ben D.","family":"Bax","sequence":"additional","affiliation":[{"name":"Medicines Discovery Institute, Cardiff University, Cardiff CF10 3AT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,1,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"682135","DOI":"10.3389\/fphar.2021.682135","article-title":"Pharmacodynamic Evaluation of Dosing, Bacterial Kill, and Resistance Suppression for Zoliflodacin Against Neisseria gonorrhoeae in a Dynamic Hollow Fiber Infection Model","volume":"12","author":"Jacobsson","year":"2021","journal-title":"Front. 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