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Our aim was to assess the activity of GSK1322322 against intracellular<jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">S. aureus<\/jats:named-content>using an<jats:italic>in vitro<\/jats:italic>pharmacodynamic model and, in parallel, to examine its cellular pharmacokinetics and intracellular disposition. For intracellular activity analysis, we used an established model of human THP-1 monocytes and tested one fully susceptible<jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">S. aureus<\/jats:named-content>strain (ATCC 25923) and 8 clinical strains with resistance to oxacillin, vancomycin, daptomycin, macrolides, clindamycin, linezolid, or moxifloxacin. Uptake, accumulation, release, and subcellular distribution (cell fractionation) of [<jats:sup>14<\/jats:sup>C]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<jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">S. aureus<\/jats:named-content>strains tested, disregarding their resistance phenotypes, with a maximal relative efficacy (<jats:italic>E<\/jats:italic><jats:sub>max<\/jats:sub>) of a 0.5 to 1 log<jats:sub>10<\/jats:sub>CFU decrease compared to the original inoculum within 24 h and a static concentration (<jats:italic>C<\/jats:italic><jats:sub>s<\/jats:sub>) close to its MIC in broth. Influx and efflux were very fast (&lt;5 min to equilibrium), and accumulation was about 4-fold, with no or a minimal effect of the broad-spectrum eukaryotic efflux transporter inhibitors gemfibrozil and verapamil. GSK1322322 was recovered in the cell-soluble fraction and was dissociated from the main subcellular organelles and from bacteria (in infected cells). The results of this study show that GSK1322322, as a typical novel deformylase inhibitor, may act against intracellular forms of<jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">S. aureus<\/jats:named-content>. They also suggest that GSK1322322 has the ability to freely diffuse into and out of eukaryotic cells as well as within subcellular compartments.<\/jats:p>","DOI":"10.1128\/aac.00827-15","type":"journal-article","created":{"date-parts":[[2015,7,14]],"date-time":"2015-07-14T02:24:44Z","timestamp":1436840684000},"page":"5747-5760","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":22,"title":["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"],"prefix":"10.1128","volume":"59","author":[{"given":"Fr\u00e9d\u00e9ric","family":"Peyrusson","sequence":"first","affiliation":[{"name":"Pharmacologie cellulaire et mol\u00e9culaire, Louvain Drug Research Institute, Universit\u00e9 catholique de Louvain, Brussels, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Deborah","family":"Butler","sequence":"additional","affiliation":[{"name":"GlaxoSmithKline, Collegeville, Pennsylvania, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7121-3623","authenticated-orcid":false,"given":"Paul M.","family":"Tulkens","sequence":"additional","affiliation":[{"name":"Pharmacologie cellulaire et mol\u00e9culaire, Louvain Drug Research Institute, Universit\u00e9 catholique de Louvain, Brussels, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0052-7991","authenticated-orcid":false,"given":"Fran\u00e7oise","family":"Van Bambeke","sequence":"additional","affiliation":[{"name":"Pharmacologie cellulaire et mol\u00e9culaire, Louvain Drug Research Institute, Universit\u00e9 catholique de Louvain, Brussels, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.4103\/0974-2727.119843"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1586\/14787210.2015.999668"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/dkq424"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0966-842X(00)01803-5"},{"key":"e_1_3_2_6_2","doi-asserted-by":"crossref","first-page":"266","DOI":"10.1160\/TH05-04-0235","article-title":"Mechanism and consequences of invasion of endothelial cells by Staphylococcus aureus","volume":"94","author":"Sinha B","year":"2005","unstructured":"Sinha B, Herrmann M. 2005. 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