Mechanistic Basis for the Action of New Cephalosporin Antibiotics Effective against Methicillin- and Vancomycin-resistantStaphylococcus aureus

Cosimo Fuda, Dusan Hesek, Mijoon Lee, Werner Heilmayer, Rodger Novak, Sergei B. Vakulenko, Shahriar Mobashery
2006 Journal of Biological Chemistry  
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 ␤-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
more » ... 2a. PBP 2a is refractory to the action of all commercially available ␤-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 ␤-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 (<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. Staphylococcus aureus was exquisitely sensitive to penicillins in the early years of the use of ␤-lactams in the clinic. In the 1940s, resistance to first generation penicillins emerged from a profusion of strains containing a class A ␤-lactamase. In response to the ␤-lactamase challenge, a second generation of penicillins that included methicillin was introduced in 1959. By 1961, a strain of S. aureus emerged first in the United Kingdom and subsequently in other parts of the world, which was resistant to methicillin and other ␤-lactams. This strain became known as methicillin-resistant S. aureus (MRSA). 2 The recent emergence of variants of MRSA that are resistant to glycopeptide antibiotics, such
doi:10.1074/jbc.m508846200 pmid:16459335 fatcat:4eaaisrw75adbjltohndxld5jq