Mechanistic basis for the action of new cephalosporin antibiotics effective against methicillin- and vancomycin-resistant Staphylococcus aureus.
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.
Fuda
Cosimo
C
Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN 46556, USA.
Hesek
Dusan
D
Lee
Mijoon
M
Heilmayer
Werner
W
Novak
Rodger
R
Vakulenko
Sergei B
SB
Mobashery
Shahriar
S
D000900:Anti-Bacterial Agents / Q000494:pharmacology; D001665:Binding Sites; D002473:Cell Wall / Q000378:metabolism; D002511:Cephalosporins / Q000494:pharmacology*; D002942:Circular Dichroism; D003001:Cloning, Molecular; D024881:Drug Resistance, Bacterial; D004591:Electrophoresis, Polyacrylamide Gel; D007700:Kinetics; D008712:Methicillin / Q000494:pharmacology*; D016106:Methicillin Resistance; D008956:Models, Chemical; D008968:Molecular Conformation; D046915:Penicillin-Binding Proteins / Q000737:chemistry; D011485:Protein Binding; D011487:Protein Conformation; D013211:Staphylococcus aureus / Q000187:drug effects / Q000378:metabolism*; D013997:Time Factors; D014466:Ultraviolet Rays; D014640:Vancomycin / Q000494:pharmacology*
D000900:Anti-Bacterial Agents; D002511:Cephalosporins; D046915:Penicillin-Binding Proteins; D014640:Vancomycin; D008712:Methicillin