Gepotidacin

Gepotidacin (CAS No. 1075236-89-3) is a first-in-class triazaacenaphthylene bactericidal antibiotic. Its core biological activity is inhibition of bacterial DNA replication, with bacterial DNA gyrase (Gyrase) and topoisomerase IV (Topoisomerase IV) as targets. It induces single-stranded DNA breaks via a unique binding site and remains active against fluoroquinolone-resistant strains. In terms of IC50 values, it inhibits Staphylococcus aureus gyrase-mediated DNA negative supercoiling at ~0.047 μM and relaxation of positive supercoils at ~0.6 μM, and induces single-stranded DNA breaks in this bacterium with EC50 values of about 0.13 μM (negatively supercoiled DNA) and 0.18 μM (positively supercoiled DNA), with no clearly defined antibacterial activity threshold other than the MIC. MIC data are pathogen-specific: Escherichia coli MIC90 is 2 μM; Neisseria gonorrhoeae MIC50 is 0.12 μM and MIC90 is 0.5 μM; MRSA MIC90 is 0.5 μM; Streptococcus pyogenes MIC90 is 0.25 μM. Common application concentrations: for in vitro experiments, 0.015~32 μM (antibacterial activity testing); in a hollow-fiber infection model, a free-drug AUC/MIC ratio ≥60.7 achieves a 2-log reduction in colony counts; in animal studies, doses simulating human pharmacokinetic exposure are used (rat pyelonephritis model), and a non-human primate plague model is effective. Clinically effective treatment concentrations correspond to the following doses: for uncomplicated urinary tract infection, 1500 mg orally twice daily for 5 days (plasma peak concentration 4~6 μg/mL, urine concentration exceeding plasma by 600-fold); for uncomplicated urogenital gonorrhea, two 3000 mg oral doses (10~12 hours apart). Both regimens achieve clinical symptom relief and pathogen eradication and remain effective against multidrug-resistant strains (such as ESBL-positive E. coli and fluoroquinolone-resistant N. gonorrhoeae).

References:

[1] Taylor SN, Morris DH, Avery AK, Workowski KA, Batteiger BE, Tiffany CA, Perry CR, Raychaudhuri A, Scangarella-Oman NE, Hossain M, Dumont EF. Gepotidacin for the Treatment of Uncomplicated Urogenital Gonorrhea: A Phase 2, Randomized, Dose-Ranging, Single-Oral Dose Evaluation. Clin Infect Dis. 2018 Aug 1;67(4):504-512. doi: 10.1093/cid/ciy145. PMID: 29617982; PMCID: PMC6070052.

[2] Gibson EG, Bax B, Chan PF, Osheroff N. Mechanistic and Structural Basis for the Actions of the Antibacterial Gepotidacin against Staphylococcus aureus Gyrase. ACS Infect Dis. 2019 Apr 12;5(4):570-581. doi: 10.1021/acsinfecdis.8b00315. Epub 2019 Feb 28. PMID: 30757898; PMCID: PMC6461504.

[3] Tiffany C, Dumont EF, Hossain M, Srinivasan M, Swift B. Pharmacokinetics, safety, and tolerability of gepotidacin administered as single or repeat ascending doses, in healthy adults and elderly subjects. Clin Transl Sci. 2022 Sep;15(9):2251-2264. doi: 10.1111/cts.13359. Epub 2022 Jul 13. PMID: 35769034; PMCID: PMC9468557.

[4] Perry C, Hossain M, Powell M, Raychaudhuri A, Scangarella-Oman N, Tiffany C, Xu S, Dumont E, Janmohamed S. Design of Two Phase III, Randomized, Multicenter Studies Comparing Gepotidacin with Nitrofurantoin for the Treatment of Uncomplicated Urinary Tract Infection in Female Participants. Infect Dis Ther. 2022 Dec;11(6):2297-2310. doi: 10.1007/s40121-022-00706-9. Epub 2022 Oct 21. PMID: 36271314; PMCID: PMC9589544.

[5] Watkins RR, Thapaliya D, Lemonovich TL, Bonomo RA. Gepotidacin: a novel, oral, 'first-in-class' triazaacenaphthylene antibiotic for the treatment of uncomplicated urinary tract infections and urogenital gonorrhoea. J Antimicrob Chemother. 2023 May 3;78(5):1137-1142. doi: 10.1093/jac/dkad060. PMID: 36883591.

[6] Wagenlehner F, Perry CR, Hooton TM, Scangarella-Oman NE, Millns H, Powell M, Jarvis E, Dennison J, Sheets A, Butler D, Breton J, Janmohamed S. 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. Lancet. 2024 Feb 24;403(10428):741-755. doi: 10.1016/S0140-6736(23)02196-7. Epub 2024 Feb 8. PMID: 38342126.

[7] Ross JDC, Wilson J, Workowski KA, Taylor SN, Lewis DA, Gatsi S, Flight W, Scangarella-Oman NE, Jakielaszek C, Lythgoe D, Powell M, Janmohamed S, Absalon J, Perry C. Oral gepotidacin for the treatment of uncomplicated urogenital gonorrhoea (EAGLE-1): a phase 3 randomised, open-label, non-inferiority, multicentre study. Lancet. 2025 May 3;405(10489):1608-1620. doi: 10.1016/S0140-6736(25)00628-2. Epub 2025 Apr 14. PMID: 40245902.