1. Antimicrob Agents Chemother. 2018 Mar 27;62(4). pii: e02245-17. doi:
10.1128/AAC.02245-17. Print 2018 Apr.

Cellular Pharmacokinetics and Intracellular Activity of Gepotidacin against
Staphylococcus aureus Isolates with Different Resistance Phenotypes in Models of 
Cultured Phagocytic Cells.

Peyrusson F(1), Tulkens PM(1), Van Bambeke F(2).

Author information: 
(1)Pharmacologie cellulaire et moléculaire, Louvain Drug Research Institute,
Université catholique de Louvain, Brussels, Belgium.
(2)Pharmacologie cellulaire et moléculaire, Louvain Drug Research Institute,
Université catholique de Louvain, Brussels, Belgium

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.

Copyright © 2018 Peyrusson et al.

DOI: 10.1128/AAC.02245-17 
PMID: 29358297