Cellular pharmacokinetics and intracellular activity of the novel peptide deformylase inhibitor GSK1322322 against Staphylococcus aureus laboratory and clinical strains with various resistance phenotypes. Studies with human THP-1 monocytes and J774 murine macrophages

Peyrusson, Frédéric;Butler, Déborah;Tulkens, Paul M.;Van Bambeke, Françoise
(2015) Antimicrobial Agents and Chemotherapy — Vol. 59, n° 9, p. 5747-5760 (2015)

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Authors
  • Peyrusson, FrédéricUCLouvain
    Author
  • Butler, DéborahGSK
    Author
  • Tulkens, Paul M.UCLouvain
    Author
  • Van Bambeke, Françoiseorcid-logoUCLouvain
    Author
Abstract
GSK1322322 is a peptide deformylase inhibitor active against Staphylococcus aureus strains resistant to currently marketed antibiotics. Our aim was to assess the activity of GSK1322322 against intracellular S. aureus using an in vitro pharmacodynamic model and, in parallel, to examine its cellular pharmacokinetics and intracellular disposition. For intracellular activity, we used an established model of human THP-1 monocytes and tested one fully susceptible (ATCC25923) and 8 clinical S. aureus strains with resistance to oxacillin, vancomycin,daptomycin, macrolides, clindamycin, linezolid, or moxifloxacin. Uptake, accumulation, release and subcellular distribution (cell fractionation) of [14C]-GSK1322322 were examined in uninfected murine J774 macrophages and uninfected and infected THP-1 monocytes. GSK1322322 demonstrated a uniform activity against the intracellular forms of all S. aureus strains tested, disregarding their resistance phenotypes, with a maximal relative efficacy (Emax) of 0.5-1 log10 CFU decrease over the original inoculum within 24 h and a static concentration (Cs) close to its MIC in broth. Influx and efflux were very fast (< 5 min to equilibrium) and accumulation was about 4-fold, with no or minimal effect of the broad-spectrum eukaryotic efflux transporters inhibitors gemfibrozil and verapamil. GSK1322322 was recovered in the cell soluble fraction, dissociated from the main subcellular organelles and from bacteria (in infected cells). This study shows that GSK1322322, as a typical novel deformylase inhibitor, may act against intracellular forms of S. aureus. It also suggests that GSK1322322 has the ability to freely diffuse in and out eukaryotic cells as well as within cells subcellular compartments.
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Peyrusson, F., Butler, D., Tulkens, P. M., & Van Bambeke, F. (2015). Cellular pharmacokinetics and intracellular activity of the novel peptide deformylase inhibitor GSK1322322 against Staphylococcus aureus laboratory and clinical strains with various resistance phenotypes. Studies with human THP-1 monocytes and J774 murine macrophages. Antimicrobial Agents and Chemotherapy, 59(9), 5747-5760. https://doi.org/10.1128/AAC.00827-15 (Original work published 2015)