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Antimicrobial Agents and Chemotherapy, January 2004, p. 250-261, Vol. 48, No. 1
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.1.250-261.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Peptide Deformylase Inhibitors as Antibacterial Agents: Identification of VRC3375, a Proline-3-Alkylsuccinyl Hydroxamate Derivative, by Using an Integrated Combinatorial and Medicinal Chemistry Approach

Vicuron Pharmaceuticals, Fremont, California 94555,¹ Novartis Institutes for Biomedical Research, Inc., Cambridge, Massachusetts 02139²

Received 23 April 2003/ Returned for modification 13 August 2003/ Accepted 7 October 2003

Peptide deformylase (PDF), a metallohydrolase essential for bacterial growth, is an attractive target for use in the discovery of novel antibiotics. Focused chelator-based chemical libraries were constructed and screened for inhibition of enzymatic activity, inhibition of Staphylococcus aureus growth, and cytotoxicity. Positive compounds were selected based on the results of all three assays. VRC3375 [N-hydroxy-3-R-butyl-3-(2-S-(tert-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 K_i of 0.24 nM against the Escherichia coli Ni²⁺ 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 S. aureus 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.

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