title: Interaction of tazobactam with Staphylococcus aureus PC1 beta-lactamase: a molecular modelling and enzyme kinetics study.
abstract: Tazobactam is a highly potent inhibitor of beta-lactamases. A kinetic study of its interaction with the class A Staphylococcus aureus PC1 beta-lactamase was undertaken which showed competitive inhibition with the substrate nitrocefin. When the enzyme was preincubated with inhibitor for varying lengths of time, the kinetic profile was consistent with a portion of the enzyme being irreversibly inactivated. Using the crystal structure of the enzyme a molecular modelling study revealed the likely interactions of the inhibitor at the active site of the enzyme. It was shown that a possible reaction could occur in which Ser-70 was crosslinked via a fragment of tazobactam to Lys-73. Trypsin digest experiments supported the proposed crosslinking reaction.
authors.affiliation: Pharmaceutical Sciences Institute, Aston University, Birmingham, Great Britain.
authors.forename: B J
authors.initials: BJ
authors.lastname: Denny
authors.forename: C A
authors.initials: CA
authors.lastname: Toomer
authors.forename: P A
authors.initials: PA
authors.lastname: Lambert
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D002511:Cephalosporins / Q000378:metabolism; D003198:Computer Simulation; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010397:Penicillanic Acid / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D010446:Peptide Fragments / Q000737:chemistry; D013211:Staphylococcus aureus / Q000201:enzymology*; D000078142:Tazobactam; D065093:beta-Lactamase Inhibitors; D001618:beta-Lactamases / Q000378:metabolism*
chemical_list: D002511:Cephalosporins; D010446:Peptide Fragments; D065093:beta-Lactamase Inhibitors; D010397:Penicillanic Acid; C054232:beta-lactamase PC1; D001618:beta-Lactamases; C021720:nitrocefin; D000078142:Tazobactam