Recent advances in the chemistry of beta-lactam compounds as selected active-site serine beta-lactamase inhibitors.
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.
Mascaretti
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Instituto de Química Orgánica de Síntesis (CONICET-UNR), Casilla de Correo 991, Rosario, 2000 Rosario, Argentina. iquiosra@citynet.net.ar
Danelon
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Laborde
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Mata
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Setti
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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
D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D065093:beta-Lactamase Inhibitors; D047090:beta-Lactams; D012694:Serine; D001618:beta-Lactamases