Vol.52 No.7 July 2004
Structure-based Design of New β -lactam Antibiotics
Suntory Institute for Bioorganic Research, 1-1-1 Wakayamadai,
Shimamoto-cho, Mishima-gun, Osaka, Japan
Abstract
β -lactamases acquire substrate spectrum extension by mutating residues at the substrate-binding site, whereas penicillin-binding proteins reduce the affinity with β -lactams by mutating residues at this site. Alteration in the recognition of β -lactams by these penicillin-interacting enzymes must be clarified and new β -lactams designed that have high affinity with penicillin-binding proteins and are stable against extended spectrum β -lactamases. Based on crystal structures of penicillin-binding proteins and β -lactamases, we can deduce the roles of residues at the substrate-binding site and design new β -lactams. With the aid of computational methods, faropenem, a 5, 6-trans-penem, was converted to 5, 6-cis-penems that show anti-MRSA activity and stability against β -lactamases.
Key word
β-lactamase, computer-assisted disign, crystal structure, peniscillin-binding protein, proteimics
Received
May 7, 2004
Accepted
June 15, 2004
Jpn. J. Chemother. 52 (7): 361-366, 2004
