<i>In Vitro</i> Activity of Gepotidacin (GSK2140944) against Neisseria gonorrhoeae

Abstract

Gepotidacin (formerly GSK2140944) is a novel, first-in-class, triazaacenaphthylene antibacterial that inhibits bacterial DNA gyrase and topoisomerase IV via a unique mechanism and has demonstrated <i>in vitro</i> activity against <i>Neisseria gonorrhoeae</i>, including drug-resistant strains, and also targets pathogens associated with other conventional and biothreat infections. Broth microdilution was used to evaluate the MIC and minimum bactericidal concentration (MBC) activity of gepotidacin and comparators against 25 <i>N. gonorrhoeae</i> strains (including five ciprofloxacin-nonsusceptible strains). Gepotidacin activity was also evaluated against three <i>N. gonorrhoeae</i> strains (including a ciprofloxacin-nonsusceptible strain) for resistance development, against three <i>N. gonorrhoeae</i> strains (including two tetracycline- and azithromycin-nonsusceptible strains) using time-kill kinetics and checkerboard methods, and against two <i>N. gonorrhoeae</i> strains for the investigation of postantibiotic (PAE) and subinhibitory (PAE-SME) effects. The MIC₅₀ and MIC₉₀ for gepotidacin against the 25 <i>N. gonorrhoeae</i> isolates tested were 0.12 and 0.25 μg/ml, respectively. The MBC₅₀ and MBC₉₀ for gepotidacin were 0.25 and 0.5 μg/ml, respectively. Gepotidacin was bactericidal, and single-step resistance selection studies did not recover any mutants, indicating a low rate of spontaneous single-step resistance. For combinations of gepotidacin and comparators tested using checkerboard methods, there were no instances where antagonism occurred and only one instance of synergy (with moxifloxacin; fractional inhibitory concentration, 0.375). This was not confirmed by <i>in vitro</i> time-kill studies. The PAE for gepotidacin against the wild-type strain ranged from 0.5 to >2.5 h, and the PAE-SME was >2.5 h. These <i>in vitro</i> data indicate that further study of gepotidacin is warranted for potential use in treating infections caused by <i>N. gonorrhoeae</i>.