Reduced Immunotoxicity and Preservation of Antibacterial Activity in a Releasable Side-Chain Carbapenem Antibiotic
Hugh Rosen,
*
Richard Hajdu,
Lynn Silver,
Helmut Kropp,
Karen Dorso,
Joyce Kohler,
Jon G. Sundelof,
Joann Huber,
Gail G. Hammond,
Jesse J. Jackson,
Charles J. Gill,
Randall Thompson,
Barbara
A. Pelak,
Jeffrey H. Epstein-Toney,
George Lankas,
Robert R. Wilkening,
Kenneth J. Wildonger,
Timothy A. Blizzard,
Frank P. DiNinno,
Ronald W. Ratcliffe,
James V. Heck,
John W. Kozarich,
Milton L. Hammond
A carbapenem antibiotic, L-786,392, was designed so that the side
chain that provides high-affinity binding to the penicillin-binding proteins responsible for bacterial resistance was also the structural basis for ameliorating immunopathology. Expulsion of the side chain
upon opening of the beta-lactam ring retained antibacterial activity
while safely expelling the immunodominant epitope. L-786,392 was well
tolerated in animal safety studies and had significant in vitro and in
vivo activities against methicillin- and vancomycin-resistant Staphylococci and vancomycin-resistant Enterococci.
Merck Research Laboratories, Rahway, NJ 07065, USA.
*
To whom correspondence should be addressed. E-mail:
hugh_rosen{at}merck.com
