title: Recent advances in the chemistry of beta-lactam compounds as selected active-site serine beta-lactamase inhibitors.
abstract: The b-lactamases catalyze the hydrolysis of the b-lactam bond of a variety of b-lactam antibiotics destroying their antibacterial activity. During the last decades, there has been an inexorable spread of b-lactamase genes into species that previously were not known to possess them. One approach to combat the action of the b-lactamase is to inhibit the enzyme. However, inhibition of b-lactamase alone is not sufficient. The ability to penetrate the external membrane of Gram-negative bacteria, chemical stability, pharmacokinetics and other factors are also important in determining whether an inhibitor is suitable or not for therapeutic use. This review takes recent examples of synthetic b-lactam compounds developed as active-site serine b-lactamase inhibitors, emphasizing information on their structures and their activity against Ambler classes A, C and D b-lactamases. In addition, examples based on rational design by computerized molecular modeling of crystal structure of the native enzyme and mechanism of the enzyme action are highlighted.
authors.affiliation: Instituto de Química Orgánica de Síntesis (CONICET-UNR), Casilla de Correo 991, Rosario, 2000 Rosario, Argentina. iquiosra@citynet.net.ar
authors.forename: O A
authors.initials: OA
authors.lastname: Mascaretti
authors.forename: G O
authors.initials: GO
authors.lastname: Danelon
authors.forename: M
authors.initials: M
authors.lastname: Laborde
authors.forename: E G
authors.initials: EG
authors.lastname: Mata
authors.forename: E L
authors.initials: EL
authors.lastname: Setti
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D001665:Binding Sites; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D006090:Gram-Negative Bacteria / Q000187:drug effects / Q000201:enzymology; D006868:Hydrolysis; D012694:Serine / Q000737:chemistry; D013237:Stereoisomerism; D065093:beta-Lactamase Inhibitors; D001618:beta-Lactamases / Q000737:chemistry* / Q000145:classification; D047090:beta-Lactams
chemical_list: D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D065093:beta-Lactamase Inhibitors; D047090:beta-Lactams; D012694:Serine; D001618:beta-Lactamases