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Cellular Pharmacokinetics and Intracellular Activity of Gepotidacin Against Staphylococcus Aureus Isolates With Different Resistance Phenotypes in Models of Cultured Phagocytic Cells

Cellular Pharmacokinetics and Intracellular Activity of Gepotidacin Against Staphylococcus Aureus Isolates With Different Resistance Phenotypes in Models of Cultured Phagocytic Cells

Frédéric Peyrusson, Paul M Tulkens, Françoise Van Bambeke

Antimicrob Agents Chemother. 2018 Mar 27;62(4):e02245-17.

PMID: 29358297

Abstract:

Gepotidacin (GSK2140944), a novel triazaacenaphthylene bacterial topoisomerase inhibitor, is currently in clinical development for the treatment of bacterial infections. This study examined in vitro its activity against intracellular Staphylococcus aureus (involved in the persistent character of skin and skin structure infections) by use of 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 (the apparent bacteriostatic concentration [Cs ] was reached at an extracellular concentration about 0.7× its MIC and was not affected by mechanisms of resistance to the comparators) and (ii) caused a maximal reduction of the intracellular burden (maximum effect) of about -1.6 log10 CFU (which was better than that caused by linezolid, macrolides, and daptomycin and similar to that caused by moxifloxacin). After 24 h of incubation of infected cells with antibiotics at 100× their MIC, the intracellular persisting fraction was <0.1% with moxifloxacin, 0.5% with gepotidacin, and >1% with the other drugs. The accumulation and efflux of gepotidacin in phagocytes were very fast (kin and kout, ∼0.3 min-1; the plateau was reached within 15 min) but modest (intracellular concentration-to-extracellular concentration ratio, ∼1.6). In cell fractionation studies, about 40 to 60% of the drug was recovered in the soluble fraction and ∼40% was 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.

Chemicals Related in the Paper:

Catalog Number	Product Name	CAS Number	Price
AP1136454	Oxacillin Related Compound C	1136-45-4	Price
AP168828908	Linezolid Related Compound C	168828-90-8	Price
AP612069304	Azithromycin Related Compound H	612069-30-4	Price
CS31042405	Moxifloxacin Related Compound C		Price

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