Cellular pharmacokinetics and intracellular activity of gepotidacin against Staphylococcus aureus with different resistance phenotypes in models of cultured phagocytic cells. [PublishAheadOfPrint]

Gepotidacin (GSK2140944), a novel triazaacenaphthylene bacterial topoisomerase inhibitor, is currently in clinical development for the treatment of bacterial infections. This study examines in vitro its activity against intracellular Staphylococcus aureus (involved in the persistent character of skin and skin structure infections) using a pharmacodynamic model and in relation to cellular pharmacokinetics in phagocytic cells. Compared to oxacillin, vancomycin, linezolid, daptomycin, azithromycin, and moxifloxacin, gepotidacin was (i) more potent intracellularly (C_s [apparent bacteriostatic effect] reached at an extracellular concentration of about 0.7 x its MIC and not affected by resistance mechanisms to the comparators) and (ii) caused a maximal reduction of the intracellular burden (E_max) of about -1.6 log₁₀ CFU (better than linezolid, macrolides, and daptomycin; similar to moxifloxacin). After 24 h of incubation of infected cells with antibiotics at 100 X their MIC, the intracellular persisting fraction was < 0.1 % with moxifloxacin, 0.5 % with gepotidacin and > 1 % with other drugs. Accumulation and efflux of gepotidacin in phagocytes was very fast (k_in and k_out ~0.3 min^-1; plateau reached within 15 minutes) but modest (intracellular to extracellular concentration ratio ~1.6). In cell fractionation studies, about 40-60 % of the drug was recovered in the soluble fraction and ~40% associated with lysosomes in uninfected cells. In infected cells, about 20% of cell-associated gepotidacin was recovered in a sedimentable fraction that also contained bacteria. This study highlights the potential for further study of gepotidacin to fight infections where intracellular niches may play a determining role in bacterial persistence and relapses.

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