title: In VitroActivity 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 demonstratedin vitroactivity againstNeisseria gonorrhoeae, 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 25N. gonorrhoeaestrains (including five ciprofloxacin-nonsusceptible strains). Gepotidacin activity was also evaluated against threeN. gonorrhoeaestrains (including a ciprofloxacin-nonsusceptible strain) for resistance development, against threeN. gonorrhoeaestrains (including two tetracycline- and azithromycin-nonsusceptible strains) using time-kill kinetics and checkerboard methods, and against twoN. gonorrhoeaestrains for the investigation of postantibiotic (PAE) and subinhibitory (PAE-SME) effects. The MIC50and MIC90for gepotidacin against the 25N. gonorrhoeaeisolates tested were 0.12 and 0.25 μg/ml, respectively. The MBC50and MBC90for 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 byin vitrotime-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. Thesein vitrodata indicate that further study of gepotidacin is warranted for potential use in treating infections caused byN. gonorrhoeae.
authors.affiliation: JMI Laboratories, North Liberty, Iowa, USA.
authors.forename: D J
authors.initials: DJ
authors.lastname: Farrell
authors.affiliation: JMI Laboratories, North Liberty, Iowa, USA.
authors.forename: H S
authors.initials: HS
authors.lastname: Sader
authors.affiliation: JMI Laboratories, North Liberty, Iowa, USA.
authors.forename: P R
authors.initials: PR
authors.lastname: Rhomberg
authors.affiliation: GlaxoSmithKline, Collegeville, Pennsylvania, USA.
authors.forename: N E
authors.initials: NE
authors.lastname: Scangarella-Oman
authors.affiliation: JMI Laboratories, North Liberty, Iowa, USA robert-flamm@jmilabs.com.
authors.forename: R K
authors.initials: RK
authors.lastname: Flamm
mesh_terms: D000073:Acenaphthenes / Q000494:pharmacology*; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D027101:DNA Topoisomerase IV / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D024901:Drug Resistance, Multiple, Bacterial / Q000187:drug effects; D015870:Gene Expression; D006069:Gonorrhea / Q000188:drug therapy / Q000382:microbiology; D006575:Heterocyclic Compounds, 3-Ring / Q000494:pharmacology*; D006801:Humans; D008826:Microbial Sensitivity Tests; D009344:Neisseria gonorrhoeae / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development / Q000302:isolation & purification; D059003:Topoisomerase Inhibitors / Q000494:pharmacology*
chemical_list: D000073:Acenaphthenes; D000900:Anti-Bacterial Agents; D006575:Heterocyclic Compounds, 3-Ring; D059003:Topoisomerase Inhibitors; C000612856:gepotidacin; D027101:DNA Topoisomerase IV
keywords: Neisseria gonorrhoeae; minimum bactericidal activity; postantibiotic effect