Characterization of gepotidacin activity, including in vitro kill kinetics, checkerboard, and PAE/SME testing against gram-positive and gram-negative bacteria
Abstract
Gepotidacin is a novel, first-in-class triazaacenaphthylene antibiotic that inhibits bacterial DNA replication through a distinct binding site and unique mechanism of action that provides well-balanced inhibition of two different type II topoisomerase enzymes (DNA gyrase and topoisomerase IV) for most pathogens. Gepotidacin was recently approved by the US Food and Drug Administration (FDA) and the Medicines and Healthcare Products Regulatory Agency (MHRA) for the treatment of uncomplicated urinary tract infections (uUTI) and by the FDA for uncomplicated urogenital gonorrhea. This study investigated the in vitro time-kill kinetics, post-antibiotic effect (PAE), and sub-inhibitory MIC effect (PAE-SME) of gepotidacin, as well as interactions between gepotidacin and select marketed antibacterial agents for species where the published activity of gepotidacin was limited. Species included are those known to be associated with uUTI: Citrobacter freundii species complex, Enterobacter cloacae species complex, Klebsiella aerogenes, Klebsiella pneumoniae, Proteus mirabilis, Providencia rettgeri, Enterococcus faecalis, and Staphylococcus saprophyticus. Isolates were selected to represent various phenotypes, including wild type, extended-spectrum beta-lactamase positive (ESBL), and fluoroquinolone-resistant. Gepotidacin displayed concentration-dependent activity in time-kill, PAE, and PAE-SME experiments. Gepotidacin displayed bactericidal activity, often by 8 h, against 83% of isolates…
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