Abstract
Phosphonate monoesters with the general structure: [formula: see text] are inhibitors of representative class A and class C beta-lactamases. This result extends the range of this type of inhibitor to the class A enzymes. Compounds where X is an electron-withdrawing substituent are better inhibitors than the unsubstituted analogue (X = H), and enzyme inhibition is concerted with stoichiometric release of the substituted phenol. Slow turnover of the phosphonates also occurs. These observations support the proposition that the mechanism of action of these inhibitors involves phosphorylation of the beta-lactamase active site. The inhibitory ability of these phosphonates suggests that the beta-lactamase active site is very effective at stabilizing negatively charged transition states. One of the compounds described also inactivated the Streptomyces R61 D-alanyl-D-alanine carboxypeptidase/transpeptidase.
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Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Ambler R. P. The structure of beta-lactamases. Philos Trans R Soc Lond B Biol Sci. 1980 May 16;289(1036):321–331. doi: 10.1098/rstb.1980.0049. [DOI] [PubMed] [Google Scholar]
- Bush K. Recent developments in beta-lactamase research and their implications for the future. Rev Infect Dis. 1988 Jul-Aug;10(4):681–690. doi: 10.1093/clinids/10.4.681. [DOI] [PubMed] [Google Scholar]
- Dideberg O., Charlier P., Wéry J. P., Dehottay P., Dusart J., Erpicum T., Frère J. M., Ghuysen J. M. The crystal structure of the beta-lactamase of Streptomyces albus G at 0.3 nm resolution. Biochem J. 1987 Aug 1;245(3):911–913. doi: 10.1042/bj2450911. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Ghuysen J. M., Frère J. M., Leyh-Bouille M., Coyette J., Dusart J., Nguyen-Distèche M. Use of model enzymes in the determination of the mode of action of penicillins and delta 3-cephalosporins. Annu Rev Biochem. 1979;48:73–101. doi: 10.1146/annurev.bi.48.070179.000445. [DOI] [PubMed] [Google Scholar]
- Govardhan C. P., Pratt R. F. Kinetics and mechanism of the serine beta-lactamase catalyzed hydrolysis of depsipeptides. Biochemistry. 1987 Jun 16;26(12):3385–3395. doi: 10.1021/bi00386a021. [DOI] [PubMed] [Google Scholar]
- Herzberg O., Moult J. Bacterial resistance to beta-lactam antibiotics: crystal structure of beta-lactamase from Staphylococcus aureus PC1 at 2.5 A resolution. Science. 1987 May 8;236(4802):694–701. doi: 10.1126/science.3107125. [DOI] [PubMed] [Google Scholar]
- Johnson M. L., Halvorson H. R., Ackers G. K. Oxygenation-linked subunit interactions in human hemoglobin: analysis of linkage functions for constituent energy terms. Biochemistry. 1976 Nov 30;15(24):5363–5371. doi: 10.1021/bi00669a024. [DOI] [PubMed] [Google Scholar]
- Knap A. K., Pratt R. F. Inactivation of the RTEM-1 cysteine beta-lactamase by iodoacetate. The nature of active-site functional groups and comparisons with the native enzyme. Biochem J. 1991 Jan 1;273(Pt 1):85–91. doi: 10.1042/bj2730085. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Moews P. C., Knox J. R., Dideberg O., Charlier P., Frère J. M. Beta-lactamase of Bacillus licheniformis 749/C at 2 A resolution. Proteins. 1990;7(2):156–171. doi: 10.1002/prot.340070205. [DOI] [PubMed] [Google Scholar]
- Murphy B. P., Pratt R. F. Evidence for an oxyanion hole in serine beta-lactamases and DD-peptidases. Biochem J. 1988 Dec 1;256(2):669–672. doi: 10.1042/bj2560669. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Pratt R. F., Govardhan C. P. beta-Lactamase-catalyzed hydrolysis of acyclic depsipeptides and acyl transfer to specific amino acid acceptors. Proc Natl Acad Sci U S A. 1984 Mar;81(5):1302–1306. doi: 10.1073/pnas.81.5.1302. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Pratt R. F. Inhibition of a class C beta-lactamase by a specific phosphonate monoester. Science. 1989 Nov 17;246(4932):917–919. doi: 10.1126/science.2814513. [DOI] [PubMed] [Google Scholar]
- Sanders C. C., Sanders W. E., Jr Microbial resistance to newer generation beta-lactam antibiotics: clinical and laboratory implications. J Infect Dis. 1985 Mar;151(3):399–406. doi: 10.1093/infdis/151.3.399. [DOI] [PubMed] [Google Scholar]
- Waley S. G. A spectrophotometric assay of beta-lactamase action on penicillins. Biochem J. 1974 Jun;139(3):789–790. doi: 10.1042/bj1390789. [DOI] [PMC free article] [PubMed] [Google Scholar]