Mechanistic Basis for the Action of New Cephalosporin Antibiotics Effective Against Methicillin- and Vancomycin-resistant Staphylococcus Aureus.
From: Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN 46556, USA.
The Journal of biological chemistry
- Publish Date: Apr 2006
- ISSN: 0021-9258
- Volume: 281
- Issue: 15
- Pages: 10035-41
- Medium: Print
- Language: English
- Citation (JAMA): Fuda Cosimo, Hesek Dusan, Lee Mijoon, et al. Mechanistic Basis for the Action of New Cephalosporin Antibiotics Effective Against Methicillin- and Vancomycin-resistant Staphylococcus Aureus.. J. Biol. Chem. Apr 2006;281:10035-41
Abstract
Emergence of methicillin-resistant Staphylococcus aureus (MRSA) has created challenges in treatment of nosocomial infections. The recent clinical emergence of vancomycin-resistant MRSA is a new disconcerting chapter in the evolution of these strains. S. aureus normally produces four PBPs, which are susceptible to modification by beta-lactam antibiotics, an event that leads to bacterial death. The gene product of mecA from MRSA is a penicillin-binding protein (PBP) designated PBP 2a. PBP 2a is refractory to the action of all commercially available beta-lactam antibiotics. Furthermore, PBP 2a is capable of taking over the functions of the other PBPs of S. aureus in the face of the challenge by beta-lactam antibiotics. Three cephalosporins (compounds 1-3) have been studied herein, which show antibacterial activities against MRSA, including the clinically important vancomycin-resistant strains. These cephalosporins exhibit substantially smaller dissociation constants for the preacylation complex compared with the case of typical cephalosporins, but their pseudo-second-order rate constants for encounter with PBP 2a (k(2)/K(s)) are not very large (< or =200 m(-1) s(-1)). It is documented herein that these cephalosporins facilitate a conformational change in PBP 2a, a process that is enhanced in the presence of a synthetic surrogate for cell wall, resulting in increases in the k(2)/K(s) parameter and in more facile enzyme inhibition. These findings argue that the novel cephalosporins are able to co-opt interactions between PBP 2a and the cell wall in gaining access to the active site in the inhibition process, a set of events that leads to effective inhibition of PBP 2a and the attendant killing of the MRSA strains.
Mesh Headings (Keywords): Anti-Bacterial Agents, Binding Sites, Cell Wall, Cephalosporins, Circular Dichroism, Cloning, Molecular, Drug Resistance, Bacterial, Electrophoresis, Polyacrylamide Gel, Kinetics, Methicillin, Methicillin Resistance, Models, Chemical, Molecular Conformation, Penicillin-Binding Proteins, Protein Binding, Protein Conformation, Staphylococcus aureus, Time Factors, Ultraviolet Rays, Vancomycin
Check for Full Text / PubMed Unique Identifier (PMID): 16459335
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