{"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":1791356985820,"version":"4.3.1"},"reference-count":75,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2026,1,3]],"date-time":"2026-01-03T00:00:00Z","timestamp":1767398400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["R01 GM126363"],"award-info":[{"award-number":["R01 GM126363"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["R01 AI170546"],"award-info":[{"award-number":["R01 AI170546"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The essential bacterial type II topoisomerases gyrase and topoisomerase IV have been exploited as the therapeutic targets of fluoroquinolone antibacterials for over four decades. Despite their broad utility, the effectiveness of fluoroquinolones has been increasingly undermined by the widespread emergence of target-mediated resistance, highlighting the need for alternative therapeutic strategies. Recent advances have produced two mechanistically distinct classes of gyrase\/topoisomerase IV-targeted antibacterials: the triazaacenaphthylenes and the spiropyrimidinetriones. The first-in-class agents gepotidacin and zoliflodacin, respectively, were approved for human use in 2025, representing the first new antibacterial classes targeting these enzymes in decades. This commentary examines the mechanisms of action of these agents, contrasts their interactions with gyrase and topoisomerase IV relative to fluoroquinolones, and considers their potential to address resistance while preserving the long-term clinical viability of therapy directed against the bacterial type II topoisomerases.<\/jats:p>","DOI":"10.3390\/ijms27010496","type":"journal-article","created":{"date-parts":[[2026,1,5]],"date-time":"2026-01-05T12:38:56Z","timestamp":1767616736000},"page":"496","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Gyrase and Topoisomerase IV as Antibacterial Targets for Gepotidacin and Zoliflodacin: Teaching Old Enzymes New Tricks"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2550-4884","authenticated-orcid":false,"given":"Neil","family":"Osheroff","sequence":"first","affiliation":[{"name":"Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN 37232, USA"},{"name":"Department of Medicine (Hematology\/Oncology), Vanderbilt University School of Medicine, Nashville, TN 37232, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,1,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1146\/annurev-biochem-061809-100002","article-title":"New mechanistic and functional insights into DNA topoisomerases","volume":"82","author":"Chen","year":"2013","journal-title":"Annu. Rev. Biochem."},{"key":"ref_2","unstructured":"Drlica, K., Shlaes, D., and Fong, I.W. (2018). Fluoroquinolone interactions with bacterial type II topoisomerases and target-mediated drug resistance. Antimicrobial Resistance in the 21st Century, Springer Nature. [2nd ed.]."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Adams, C.C., Gordon, C.M., Jones, V.F.R., Kauffman, L.H., Lambropoulou, S., Millet, K.C., Przytycki, J.H., Ricca, R., and Sazdanovic, R. (2019). Regulation of DNA by topoisomerases: Mathematics at the molecular level. Knots, Low-Dimensional Topology and Applications, Springer Nature.","DOI":"10.1007\/978-3-030-16031-9"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Bush, N.G., Diez-Santos, I., Abbott, L.R., and Maxwell, A. (2020). Quinolones: Mechanism, lethality and their contributions to antibiotic resistance. Molecules, 25.","DOI":"10.3390\/molecules25235662"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2000286","DOI":"10.1002\/bies.202000286","article-title":"DNA topoisomerases: Advances in understanding of cellular roles and multi-protein complexes via structure-function analysis","volume":"43","author":"McKie","year":"2021","journal-title":"Bioessays"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1097","DOI":"10.1021\/acsinfecdis.4c00128","article-title":"Gyrase and topoisomerase IV: Recycling old targets for new antibacterials to combat fluoroquinolone resistance","volume":"10","author":"Collins","year":"2024","journal-title":"ACS Infect. Dis."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1565","DOI":"10.1021\/bi5000564","article-title":"Mechanism of quinolone action and resistance","volume":"53","author":"Aldred","year":"2014","journal-title":"Biochemistry"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1113","DOI":"10.1128\/AAC.32.8.1113","article-title":"Association between early inhibition of DNA synthesis and the MICs and MBCs of carboxyquinolone antimicrobial agents for wild-type and mutant [gyrA nfxB(ompF) acrA] Escherichia coli K-12","volume":"32","author":"Chow","year":"1988","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1021\/cb300648v","article-title":"Drugging topoisomerases: Lessons and challenges","volume":"8","author":"Pommier","year":"2013","journal-title":"ACS Chem. Biol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1111\/nyas.12830","article-title":"Mechanisms of drug resistance: Quinolone resistance","volume":"1354","author":"Hooper","year":"2015","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1007\/978-1-4939-7459-7_3","article-title":"DNA topoisomerases as targets for antibacterial agents","volume":"Volume 1703","author":"Drolet","year":"2018","journal-title":"DNA Topoisomerases"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1719","DOI":"10.1039\/C9MD00120D","article-title":"Quinolone antibiotics","volume":"10","author":"Pham","year":"2019","journal-title":"Med. Chem. Commun."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"3427","DOI":"10.1016\/j.jmb.2019.07.008","article-title":"DNA topoisomerase inhibitors: Trapping a DNA-cleaving machine in motion","volume":"431","author":"Bax","year":"2019","journal-title":"J. Mol. Biol."},{"key":"ref_14","unstructured":"Centers for Disease Control and Prevention (2017). Outpatient Antibiotic Prescriptions\u2014United States, 2017."},{"key":"ref_15","unstructured":"Fisher, J.F., Mobashery, S., and Miller, M.J. (2018). Four ways to skin a cat: Inhibition of bacterial topoisomerases leading to the clinic. Antibacterials: Volume I, Springer Nature."},{"key":"ref_16","unstructured":"WHO Advisory Group on Integrated Surveillance of Antimicrobial Resistance (2019). Critically Important Antimicrobials for Human Medicine, 6th Revision."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"e0015121","DOI":"10.1128\/AAC.00151-21","article-title":"Outpatient fluoroquinolone prescription fills in the United States, 2014 to 2020: Assessing the impact of Food and Drug Administration safety warnings","volume":"65","author":"Buehrle","year":"2021","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1152","DOI":"10.1038\/nsmb.1892","article-title":"Structural basis of quinolone inhibition of type IIA topoisomerases and target-mediated resistance","volume":"17","author":"Wohlkonig","year":"2010","journal-title":"Nat. Struct. Mol. Biol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/BF00338386","article-title":"Quinolone-resistant mutations of the gyrA gene of Escherichia coli","volume":"211","author":"Yoshida","year":"1988","journal-title":"Mol. Gen. Genet."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"886","DOI":"10.1128\/AAC.33.6.886","article-title":"Cloning and characterization of a DNA gyrase A gene from Escherichia coli that confers clinical resistance to 4-quinolones","volume":"33","author":"Cullen","year":"1989","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"696","DOI":"10.1128\/AAC.37.4.696","article-title":"Mutations in the gyrA gene of a highly fluoroquinolone-resistant clinical isolate of Escherichia coli","volume":"37","author":"Heisig","year":"1993","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"370","DOI":"10.1021\/bi2013905","article-title":"Drug interactions with Bacillus anthracis topoisomerase IV: Biochemical basis for quinolone action and resistance","volume":"51","author":"Aldred","year":"2012","journal-title":"Biochemistry"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"4628","DOI":"10.1093\/nar\/gkt124","article-title":"Topoisomerase IV-quinolone interactions are mediated through a water-metal ion bridge: Mechanistic basis of quinolone resistance","volume":"41","author":"Aldred","year":"2013","journal-title":"Nucleic Acids Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"5558","DOI":"10.1021\/bi500682e","article-title":"Role of the water-metal ion bridge in mediating interactions between quinolones and Escherichia coli topoisomerase IV","volume":"53","author":"Aldred","year":"2014","journal-title":"Biochemistry"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Carter, H.E., Wildman, B., Schwanz, H.A., Kerns, R.J., and Aldred, K.J. (2023). Role of the water-metal ion bridge in quinolone interactions with Escherichia coli gyrase. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24032879"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"438","DOI":"10.1016\/j.tim.2014.04.007","article-title":"Fluoroquinolone resistance: Mechanisms, impact on bacteria, and role in evolutionary success","volume":"22","author":"Redgrave","year":"2014","journal-title":"Trends Microbiol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1554","DOI":"10.1128\/AAC.39.7.1554","article-title":"Analysis of gyrA and grlA mutations in stepwise-selected ciprofloxacin-resistant mutants of Staphylococcus aureus","volume":"39","author":"Ferrero","year":"1995","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2321","DOI":"10.1128\/AAC.40.10.2321","article-title":"Involvement of topoisomerase IV and DNA gyrase as ciprofloxacin targets in Streptococcus pneumoniae","volume":"40","author":"Pan","year":"1996","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2160","DOI":"10.1128\/AAC.44.8.2160-2165.2000","article-title":"Selective targeting of topoisomerase IV and DNA gyrase in Staphylococcus aureus: Different patterns of quinolone-induced inhibition of DNA synthesis","volume":"44","author":"Fournier","year":"2000","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"935","DOI":"10.1038\/nature09197","article-title":"Type IIA topoisomerase inhibition by a new class of antibacterial agents","volume":"466","author":"Bax","year":"2010","journal-title":"Nature"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"570","DOI":"10.1021\/acsinfecdis.8b00315","article-title":"Mechanistic and structural basis for the actions of the antibacterial gepotidacin against Staphylococcus aureus gyrase","volume":"5","author":"Gibson","year":"2019","journal-title":"ACS Infect. Dis."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"4935","DOI":"10.1038\/s41467-019-12914-y","article-title":"Cryo-EM structure of the complete E. coli DNA gyrase nucleoprotein complex","volume":"10","author":"Lotz","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1137","DOI":"10.1021\/acsinfecdis.3c00346","article-title":"Interactions between gepotidacin and Escherichia coli gyrase and topoisomerase IV: Genetic and biochemical evidence for well-balanced dual targeting","volume":"10","author":"Oviatt","year":"2024","journal-title":"ACS Infect. Dis."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"2446","DOI":"10.1021\/acsmedchemlett.0c00428","article-title":"Dioxane-linked amide derivatives as novel bacterial topoisomerase inhibitors against gram-positive Staphylococcus aureus","volume":"11","author":"Lu","year":"2020","journal-title":"ACS Med. Chem. Lett."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"955","DOI":"10.1021\/acsmedchemlett.2c00111","article-title":"1,3-Dioxane-linked novel bacterial topoisomerase inhibitors: Expanding structural diversity and the antibacterial spectrum","volume":"13","author":"Lu","year":"2022","journal-title":"ACS Med. Chem. Lett."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"3093","DOI":"10.1021\/acsinfecdis.5c00497","article-title":"Mechanism of action of gepotidacin: Well-balanced dual-targeting against Neisseria gonorrhoeae gyrase and topoisomerase IV in cells and in vitro","volume":"11","author":"Oviatt","year":"2025","journal-title":"ACS Infect. Dis."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Mann, C.A., Halasohoris, S.A., Gray, A.M., Chua, J., Spencer, J.L., Curry, B.J., Babyak, A.L., Klimko, C.P., Cote, C.K., and West, J.S. (2025). Activities of the novel bacterial topoisomerase inhibitor OSUAB-0284 against the biothreat pathogen Bacillus anthracis and its type II topoisomerases. ACS Infec. Dis., in press.","DOI":"10.1021\/acsinfecdis.5c00860"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1128\/AAC.04077-14","article-title":"Target-based resistance in Pseudomonas aeruginosa and Escherichia coli to NBTI 5463, a novel bacterial type II topoisomerase inhibitor","volume":"59","author":"Nayar","year":"2015","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"e00207-19","DOI":"10.1128\/AAC.00207-19","article-title":"Rapid evolution of reduced susceptibility against a balanced dual-targeting antibiotic through stepping-stone mutations","volume":"63","author":"Szili","year":"2019","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1608","DOI":"10.1016\/S0140-6736(25)00628-2","article-title":"Oral gepotidacin for the treatment of uncomplicated urogenital gonorrhoea (EAGLE-1): A phase 3 randomised, open-label, non-inferiority, multicentre study","volume":"405","author":"Ross","year":"2025","journal-title":"Lancet"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"741","DOI":"10.1016\/S0140-6736(23)02196-7","article-title":"Oral gepotidacin versus nitrofurantoin in patients with uncomplicated urinary tract infection (EAGLE-2 and EAGLE-3): Two randomised, controlled, double-blind, double-dummy, phase 3, non-inferiority trials","volume":"403","author":"Wagenlehner","year":"2024","journal-title":"Lancet"},{"key":"ref_42","first-page":"322","article-title":"New antibiotic for urinary tract infections nabs FDA approval","volume":"24","author":"Mullard","year":"2025","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_43","unstructured":"(2025, March 25). GlaxoSmithKline Blujepa (Gepotidacin) Approved by US FDA for Treatment of Uncomplicated Urinary Tract Infections (uUTIs) in Female Adults and Paediatric Patients 12 Years of Age and Older. Available online: https:\/\/www.gsk.com\/en-gb\/media\/press-releases\/blujepa-gepotidacin-approved-by-us-fda-for-treatment-of-uncomplicated-urinary-tract-infections\/."},{"key":"ref_44","unstructured":"Medicines and Healthcare Products Regulatory Agency (2025, August 28). MHRA Approves UK\u2019s First New Type of Antibiotic for Urinary Tract Infections in Nearly 30 Years, Available online: https:\/\/www.gov.uk\/government\/news\/mhra-approves-uks-first-new-type-of-antibiotic-for-urinary-tract-infections-in-nearly-30-years."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"ofw281","DOI":"10.1093\/ofid\/ofw281","article-title":"The increase in hospitalizations for urinary tract infections and the associated costs in the United States, 1998\u20132011","volume":"4","author":"Simmering","year":"2017","journal-title":"Open Forum Infect. Dis."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1756287219832172","DOI":"10.1177\/1756287219832172","article-title":"An introduction to the epidemiology and burden of urinary tract infections","volume":"11","author":"Medina","year":"2019","journal-title":"Ther. Adv. Urol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"2669","DOI":"10.1007\/s00345-019-03071-4","article-title":"Epidemiology of urological infections: A global burden","volume":"38","author":"Ozturk","year":"2020","journal-title":"World J. Urol."},{"key":"ref_48","unstructured":"(2025, December 11). GlaxoSmithKline Blujepa (Gepotidacin) Approved by US FDA as Oral Option for Treatment of Uncomplicated Urogenital Gonorrhoea (uGC). Available online: https:\/\/www.gsk.com\/en-gb\/media\/press-releases\/blujepa-gepotidacin-approved-by-us-fda-as-oral-option-for-treatment-of-uncomplicated-urogenital-gonorrhoea-ugc\/."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"226","DOI":"10.1038\/nrmicro.2017.169","article-title":"Neisseria gonorrhoeae host adaptation and pathogenesis","volume":"16","author":"Quillin","year":"2018","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_50","unstructured":"World Health Organization (2021). Web annex 1: Key data at a glance, Global Progress Report on HIV, Viral Hepatitis and Sexually Transmitted Infections, 2021."},{"key":"ref_51","unstructured":"World Health Organization (2023). Gonorrhoea (Neisseria gonorrhoeae Infection)."},{"key":"ref_52","unstructured":"Koebler, J. (2023, November 12). World Health Organization Warns Gonorrhea Could Join HIV as \u2018Uncurable\u2019. Available online: https:\/\/www.usnews.com\/news\/articles\/2012\/06\/06\/world-health-organization-warns-gonorrhea-could-join-hiv-as-uncurable-."},{"key":"ref_53","unstructured":"World Health Organization (2024). WHO Bacterial Priority Pathogens List, 2024: Bacterial Pathogens of Public Health Importance to Guide Research, Development and Strategies to Prevent and Control Antimicrobial Resistance."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1038\/s41572-019-0128-6","article-title":"Gonorrhoea","volume":"5","author":"Unemo","year":"2019","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1093\/clinids\/20.Supplement_1.S47","article-title":"Drugs of choice for the treatment of uncomplicated gonococcal infections","volume":"20","author":"Moran","year":"1995","journal-title":"Clin. Infect. Dis."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"829","DOI":"10.1517\/14656566.5.4.829","article-title":"The use of fluoroquinolones in gonorrhoea: The increasing problem of resistance","volume":"5","author":"Dan","year":"2004","journal-title":"Expert Opin. Pharmacother."},{"key":"ref_57","unstructured":"Centers for Disease Control and Prevention (2007). Update to CDC\u2019s sexually transmitted diseases treatment guidelines, 2006: Fluoroquinolones no longer recommended for treatment of gonococcal infections. MMWR Morb. Mortal. Wkly. Rep., 56, 332\u2013336."},{"key":"ref_58","unstructured":"National Center for Health Statistics (2023). Health, United States, 2020\u20132021: Annual Perspective."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"e627","DOI":"10.1016\/S2666-5247(21)00171-3","article-title":"WHO global antimicrobial resistance surveillance for Neisseria gonorrhoeae 2017-18: A retrospective observational study","volume":"2","author":"Unemo","year":"2021","journal-title":"Lancet Microbe"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"10048","DOI":"10.1038\/ncomms10048","article-title":"Structural basis of DNA gyrase inhibition by antibacterial QPT-1, anticancer drug etoposide and moxifloxacin","volume":"6","author":"Chan","year":"2015","journal-title":"Nat. Commun."},{"key":"ref_61","doi-asserted-by":"crossref","unstructured":"Morgan, H., Lipka-Lloyd, M., Warren, A.J., Hughes, N., Holmes, J., Burton, N.P., Mahenthiralingam, E., and Bax, B.D. (2023). A 2.8 \u00c5 structure of zoliflodacin in a DNA cleavage complex with Staphylococcus aureus DNA gyrase. Int. J. Mol. Sci., 24.","DOI":"10.1101\/2022.11.30.518515"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"20984","DOI":"10.1074\/jbc.M115.663534","article-title":"Inhibition of Neisseria gonorrhoeae type II topoisomerases by the novel spiropyrimidinetrione AZD0914","volume":"290","author":"Kern","year":"2015","journal-title":"J. Biol. Chem."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"3071","DOI":"10.1021\/acsinfecdis.4c00438","article-title":"Interactions between zoliflodacin and Neisseria gonorrhoeae gyrase and topoisomerase IV: Enzymological basis for cellular targeting","volume":"10","author":"Collins","year":"2024","journal-title":"ACS Infect. Dis."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1478","DOI":"10.1128\/AAC.04456-14","article-title":"Characterization of the novel DNA gyrase inhibitor AZD0914: Low resistance potential and lack of cross-resistance in Neisseria gonorrhoeae","volume":"59","author":"Alm","year":"2015","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1128\/AAC.04124-14","article-title":"In vitro antibacterial activity of AZD0914, a new spiropyrimidinetrione DNA gyrase\/topoisomerase inhibitor with potent activity against Gram-positive, fastidious Gram-negative, and atypical bacteria","volume":"59","author":"Huband","year":"2015","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"5220","DOI":"10.1128\/AAC.00786-15","article-title":"High in vitro susceptibility to the novel spiropyrimidinetrione ETX0914 (AZD0914) among 873 contemporary clinical Neisseria gonorrhoeae isolates from 21 European countries from 2012 to 2014","volume":"59","author":"Unemo","year":"2015","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"1918","DOI":"10.1128\/AAC.02820-15","article-title":"In vitro activity of gepotidacin, a novel triazaacenaphthylene bacterial topoisomerase inhibitor, against a broad spectrum of bacterial pathogens","volume":"60","author":"Biedenbach","year":"2016","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"328","DOI":"10.1016\/j.ijantimicag.2016.05.018","article-title":"In vitro growth of multidrug-resistant Neisseria gonorrhoeae isolates is inhibited by ETX0914, a novel spiropyrimidinetrione","volume":"48","author":"Papp","year":"2016","journal-title":"Int. J. Antimicrob. Agents"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"1221","DOI":"10.1093\/jac\/dkab024","article-title":"High susceptibility to zoliflodacin and conserved target (GyrB) for zoliflodacin among 1209 consecutive clinical Neisseria gonorrhoeae isolates from 25 European countries, 2018","volume":"76","author":"Unemo","year":"2021","journal-title":"J. Antimicrob. Chemother."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"6903","DOI":"10.1021\/acs.jmedchem.2c00266","article-title":"Spiropyrimidinetrione DNA gyrase inhibitors with potent and selective antituberculosis activity","volume":"65","author":"Govender","year":"2022","journal-title":"J. Med. Chem."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"e0219221","DOI":"10.1128\/aac.02192-21","article-title":"Spiropyrimidinetriones: A class of DNA gyrase inhibitors with activity against Mycobacterium tuberculosis and without cross-resistance to fluoroquinolones","volume":"66","author":"Basarab","year":"2022","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"706","DOI":"10.1021\/acsinfecdis.3c00012","article-title":"A series of spiropyrimidinetriones that enhances DNA cleavage mediated by Mycobacterium tuberculosis gyrase","volume":"9","author":"Byl","year":"2023","journal-title":"ACS Infect. Dis."},{"key":"ref_73","doi-asserted-by":"crossref","unstructured":"Luckey, A., Balasegaram, M., Barbee, L.A., Batteiger, T.A., Broadhurst, H., Cohen, S.E., Delany-Moretlwe, S., de Vries, H.J.C., Dionne, J.A., and Gill, K. (2025). Zoliflodacin versus ceftriaxone plus azithromycin for treatment of uncomplicated urogenital gonorrhoea: An international, randomised, controlled, open-label, phase 3, non-inferiority clinical trial. Lancet.","DOI":"10.1016\/S0140-6736(25)01953-1"},{"key":"ref_74","unstructured":"Global Antibiotic Research & Development Partnership (2025, December 12). NUZOLVENCE\u00ae (Zoliflodacin), First-in-Class Oral Antibiotic for Gonorrhoea, Receives U.S. FDA Approval. Available online: https:\/\/gardp.org\/nuzolvence-zoliflodacin-first-in-class-oral-antibiotic-for-gonorrhoea-receives-u-s-fda-approval\/."},{"key":"ref_75","unstructured":"U.S. Food and Drug Administration (2025, December 12). FDA Approves Two Oral Therapies to Treat Gonorrhea, Available online: https:\/\/www.fda.gov\/news-events\/press-announcements\/fda-approves-two-oral-therapies-treat-gonorrhea."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/1\/496\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,7]],"date-time":"2026-01-07T05:16:50Z","timestamp":1767763010000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/1\/496"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,1,3]]},"references-count":75,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,1]]}},"alternative-id":["ijms27010496"],"URL":"https:\/\/doi.org\/10.3390\/ijms27010496","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,1,3]]}}}