Evaluation of inhibition of the carbenicillin‐hydrolyzing β‐lactamase PSE‐4 by the clinically used mechanism‐based inhibitors
- 27 March 2000
- journal article
- research article
- Published by Wiley in FEBS Letters
- Vol. 470 (3), 285-292
- https://doi.org/10.1016/s0014-5793(00)01342-9
Abstract
Characterization of the biochemical steps in the inactivation chemistry of clavulanic acid, sulbactam and tazobactam with the carbenicillin-hydrolyzing β-lactamase PSE-4 from Pseudomonas aeruginosa is described. Although tazobactam showed the highest affinity to the enzyme, all three inactivators were excellent inhibitors for this enzyme. Transient inhibition was observed for the three inactivators before the onset of irreversible inactivation of the enzyme. Partition ratios ( k cat / k inact ) of 11, 41 and 131 were obtained with clavulanic acid, tazobactam and sulbactam, respectively. Furthermore, these values were found to be 14-fold, 3-fold and 80-fold lower, respectively, than the values obtained for the clinically important TEM-1 β-lactamase. The kinetic findings were put in perspective by determining the computational models for the pre-acylation complexes and the immediate acyl-enzyme intermediates for all three inactivators. A discussion of the pertinent structural factors is presented, with PSE-4 showing subtle differences in interactions with the three inhibitors compared to the TEM-1 enzyme.Keywords
This publication has 40 references indexed in Scilit:
- Resistance Mechanisms inPseudomonas aeruginosaand Other Nonfermentative Gram‐Negative BacteriaClinical Infectious Diseases, 1998
- Carbenicillin‐hydrolysing penicillinase mediated by a plasmid of Proteus mirabilis and its relationship to the PSE‐type enzymes of Pseudomonas aeruginosa Journal of Applied Microbiology, 1997
- Structural Insights into the Catalytic Domains of Human Matrix Metalloprotease-2 and Human Matrix Metalloprotease-9: Implications for Substrate SpecificitiesJournal of Molecular Modeling, 1997
- Structural Basis of Extended Spectrum TEM β-LactamasesPublished by Elsevier BV ,1996
- Crystal Structure of 6α-(Hydroxymethyl)penicillanate Complexed to the TEM-1 β-Lactamase from Escherichia coli: Evidence on the Mechanism of Action of a Novel Inhibitor Designed by a Computer-Aided ProcessJournal of the American Chemical Society, 1996
- Design, Synthesis, and Evaluation of a Potent Mechanism-Based Inhibitor for the TEM .beta.-Lactamase with Implications for the Enzyme MechanismJournal of the American Chemical Society, 1995
- Potent mechanism-based inhibition of the TEM-1 .beta.-lactamase by novel N-sulfonyloxy .beta.-lactamsJournal of the American Chemical Society, 1995
- A Structure-Based Analysis of the Inhibition of Class A .beta.-Lactamases by SulbactamBiochemistry, 1994
- Basic local alignment search toolJournal of Molecular Biology, 1990
- The differential expression of genes for the PSE-4 β-lactamase in Pseudomonas aeruginosa and the EnterobacteriaceaeJournal of Antimicrobial Chemotherapy, 1988