Peptide Deformylase Inhibitors as Antibacterial Agents: Identification of VRC3375, a Proline-3-Alkylsuccinyl Hydroxamate Derivative, by Using an Integrated Combinatorial and Medicinal Chemistry Approach
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Published:2004-01
Issue:1
Volume:48
Page:250-261
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ISSN:0066-4804
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Container-title:Antimicrobial Agents and Chemotherapy
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language:en
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Short-container-title:Antimicrob Agents Chemother
Author:
Chen D.1, Hackbarth C.1, Ni Z. J.1, Wu C.1, Wang W.1, Jain R.1, He Y.2, Bracken K.2, Weidmann B.2, Patel D. V.1, Trias J.1, White R. J.1, Yuan Z.1
Affiliation:
1. Vicuron Pharmaceuticals, Fremont, California 94555 2. Novartis Institutes for Biomedical Research, Inc., Cambridge, Massachusetts 02139
Abstract
ABSTRACT
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
Ni
2+
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.
Publisher
American Society for Microbiology
Subject
Infectious Diseases,Pharmacology (medical),Pharmacology
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