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N-alkyl urea hydroxamic acids as a new class of peptide deformylase inhibitors with antibacterial activity.

Authors :
Hackbarth CJ
Chen DZ
Lewis JG
Clark K
Mangold JB
Cramer JA
Margolis PS
Wang W
Koehn J
Wu C
Lopez S
Withers G 3rd
Gu H
Dunn E
Kulathila R
Pan SH
Porter WL
Jacobs J
Trias J
Patel DV
Weidmann B
White RJ
Yuan Z
Source :
Antimicrobial agents and chemotherapy [Antimicrob Agents Chemother] 2002 Sep; Vol. 46 (9), pp. 2752-64.
Publication Year :
2002

Abstract

Peptide deformylase (PDF) is a prokaryotic metalloenzyme that is essential for bacterial growth and is a new target for the development of antibacterial agents. All previously reported PDF inhibitors with sufficient antibacterial activity share the structural feature of a 2-substituted alkanoyl at the P(1)' site. Using a combination of iterative parallel synthesis and traditional medicinal chemistry, we have identified a new class of PDF inhibitors with N-alkyl urea at the P(1)' site. Compounds with MICs of <or=4 micro g/ml against gram-positive and gram-negative pathogens, including Staphylococcus aureus, Streptococcus pneumoniae, and Haemophilus influenzae, have been identified. The concentrations needed to inhibit 50% of enzyme activity (IC(50)s) for Escherichia coli Ni-PDF were <or=0.1 micro M, demonstrating the specificity of the inhibitors. In addition, these compounds were very selective for PDF, with IC(50)s of consistently >200 micro M for matrilysin and other mammalian metalloproteases. Structure-activity relationship analysis identified preferred substitutions resulting in improved potency and decreased cytotoxity. One of the compounds (VRC4307) was cocrystallized with PDF, and the enzyme-inhibitor structure was determined at a resolution of 1.7 A. This structural information indicated that the urea compounds adopt a binding position similar to that previously determined for succinate hydroxamates. Two compounds, VRC4232 and VRC4307, displayed in vivo efficacy in a mouse protection assay, with 50% protective doses of 30.8 and 17.9 mg/kg of body weight, respectively. These N-alkyl urea hydroxamic acids provide a starting point for identifying new PDF inhibitors that can serve as antimicrobial agents.

Details

Language :
English
ISSN :
0066-4804
Volume :
46
Issue :
9
Database :
MEDLINE
Journal :
Antimicrobial agents and chemotherapy
Publication Type :
Academic Journal
Accession number :
12183225
Full Text :
https://doi.org/10.1128/AAC.46.9.2752-2764.2002