| Autor: |
Hackbarth, Corinne J., Chen, Dawn Z., Lewis, Jason G., Clark, Kirk, Mangold, James B., Cramer, Jeffrey A., Margolis, Peter S., Wang, Wen, Koehn, Jim, Wu, Charlotte, Lopez, S., Withers, George, Gu, Helen, Dunn, Elina, Kulathila, R., Pan, Shi-Hao, Porter, Wilma L., Jacobs, Jeff, Trias, Joaquim, Patel, Dinesh V., Weidmann, Beat, White, Richard J., Yuan, Zhengyu |
| Zdroj: |
Antimicrobial Agents and Chemotherapy; September 2002, Vol. 46 Issue: 9 p2752-2764, 13p |
| Abstrakt: |
ABSTRACTPeptide 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 P1′ 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 P1′ site. Compounds with MICs of ≤4 μg/ml against gram-positive and gram-negative pathogens, including Staphylococcusaureus, Streptococcuspneumoniae, and Haemophilusinfluenzae, have been identified. The concentrations needed to inhibit 50% of enzyme activity (IC50s) for EscherichiacoliNi-PDF were ≤0.1 μM, demonstrating the specificity of the inhibitors. In addition, these compounds were very selective for PDF, with IC50s of consistently >200 μM 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 Å. 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. |
| Databáze: |
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