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Focused chelator-based chemical libraries were constructed and screened for inhibition of enzymatic activity, inhibition of<jats:italic>Staphylococcus aureus<\/jats:italic>growth, and cytotoxicity. Positive compounds were selected based on the results of all three assays. VRC3375 [<jats:italic>N<\/jats:italic>-hydroxy-3-<jats:italic>R<\/jats:italic>-butyl-3-(2-S-(<jats:italic>tert<\/jats:italic>-butoxycarbonyl)-pyrrolidin-1-ylcarbonyl)propionamide] was identified as having the most favorable properties through an integrated combinatorial and medicinal chemistry effort. This compound is a potent PDF inhibitor with a<jats:italic>K<jats:sub>i<\/jats:sub><\/jats:italic>of 0.24 nM against the<jats:italic>Escherichia coli<\/jats:italic>Ni<jats:sup>2+<\/jats:sup>enzyme, possesses activity against gram-positive and gram-negative bacterial pathogens, and has a low cytotoxicity. Mechanistic experiments demonstrate that the compound inhibits bacterial growth through PDF inhibition. Pharmacokinetic studies of this drug in mice indicate that VRC3375 is orally bioavailable and rapidly distributed among various tissues. VRC3375 has in vivo activity against<jats:italic>S. aureus<\/jats:italic>in a murine septicemia model, with 50% effective doses of 32, 17, and 21 mg\/kg of body weight after dosing by intravenous (i.v.), subcutaneous (s.c.), and oral (p.o.) administration, respectively. In murine single-dose toxicity studies, no adverse effects were observed after dosing with more than 400 mg of VRC3375 per kg by i.v., p.o., or s.c. administration. The in vivo efficacy and low toxicity of VRC3375 suggest the potential for developing this class of compounds to be used in future antibacterial drugs.<\/jats:p>","DOI":"10.1128\/aac.48.1.250-261.2004","type":"journal-article","created":{"date-parts":[[2003,12,24]],"date-time":"2003-12-24T02:03:22Z","timestamp":1072231402000},"page":"250-261","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":61,"title":["Peptide Deformylase Inhibitors as Antibacterial Agents: Identification of VRC3375, a Proline-3-Alkylsuccinyl Hydroxamate Derivative, by Using an Integrated Combinatorial and Medicinal Chemistry Approach"],"prefix":"10.1128","volume":"48","author":[{"given":"D.","family":"Chen","sequence":"first","affiliation":[{"name":"Vicuron Pharmaceuticals, Fremont, California 94555"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C.","family":"Hackbarth","sequence":"additional","affiliation":[{"name":"Vicuron Pharmaceuticals, Fremont, California 94555"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Z. 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