PMID:12183225
| Citation |
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 and Yuan, Z (2002) N-alkyl urea hydroxamic acids as a new class of peptide deformylase inhibitors with antibacterial activity. Antimicrob. Agents Chemother. 46:2752-64 |
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| 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. |
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| Keywords |
Amidohydrolases; Aminopeptidases/antagonists & inhibitors; Animals; Bacteria/drug effects; Biotransformation; Crystallography, X-Ray; DNA Primers; Drug Resistance; Drug Screening Assays, Antitumor; Escherichia coli/metabolism; Female; Haemophilus influenzae/drug effects; Haemophilus influenzae/genetics; Humans; Hydroxamic Acids/chemical synthesis; Hydroxamic Acids/pharmacokinetics; Hydroxamic Acids/pharmacology; Male; Mice; Microbial Sensitivity Tests; Microsomes, Liver/metabolism; Molecular Conformation; Protease Inhibitors/chemical synthesis; Protease Inhibitors/pharmacokinetics; Protease Inhibitors/pharmacology; Rats; Rats, Sprague-Dawley; Sepsis/drug therapy; Sepsis/microbiology; Streptococcus pneumoniae/drug effects; Streptococcus pneumoniae/genetics; Structure-Activity Relationship; Tumor Cells, Cultured; Urea/analogs & derivatives; Urea/chemical synthesis; Urea/pharmacokinetics; Urea/pharmacology |
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