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Chapter 11 : β-Lactam Compounds as β-Lactamase Inhibitors

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β-Lactam Compounds as β-Lactamase Inhibitors, Page 1 of 2

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Abstract:

An understanding of the mechanism of action and the inactivation of native and mutant β-lactamases, together with the identification of positions where amino acid substitutions occurred and the folding properties and flexibility of these enzymes, is important for the design of new effective β-lactam antibiotics as well as inhibitors of these enzymes. Scientists have identified different processes for the inactivation of Escherichia coli TEM-1 (RTEM) β-lactamase by sulbactam. First, sulbactam is a substrate in the sense that the enzyme catalyzes the hydrolytic opening of the β-lactam ring. Second, it is an enzyme inhibitor; at pH 8, about 10 molecules of inhibitor are consumed per enzyme molecule. Thus, interaction of the enzyme with sulbactam gives rise to irreversible inhibition. Clavulanic acid, sulbactam, and tazobactam inhibit exocellular β-lactamases encoded by plasmids from Staphylococcus spp. and group 2 periplasmic β-lactamases (except for some TEM mutants) of gram-negative bacteria. These β-lactamases include the TEM-1 β-lactamase, which is plasmid encoded and is one of the most common β-lactamases found in bacteria. Numerous studies have demonstrated the effectiveness of the clavulanate mixture in primary and recurrent urinary infections caused by susceptible strains of E. coli and other bacteria, including many amoxicillin-resistant strains. It has been used with good results in infections of the skin and soft tissues caused by susceptible pathogens, including β-lactamase-producing strains of Staphylococcus aureus. The broad antibacterial spectrum of piperacillin-tazobactam mixture makes it most useful for the treatment of infections in immunodepressed or neutropenic patients.

Citation: Mascaretti O. 2003. β-Lactam Compounds as β-Lactamase Inhibitors, p 159-170. In Bacteria versus Antibacterial Agents. ASM Press, Washington, DC. doi: 10.1128/9781555817794.ch11
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Figures

Image of Figure 11.1
Figure 11.1

Structure of clavulanic acid.

Citation: Mascaretti O. 2003. β-Lactam Compounds as β-Lactamase Inhibitors, p 159-170. In Bacteria versus Antibacterial Agents. ASM Press, Washington, DC. doi: 10.1128/9781555817794.ch11
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Image of Figure 11.2
Figure 11.2

Proposed mechanism for the inactivation of the TEM-2 or PC1 β-lactamase by clavulanic acid. For clarity, the residues Ser70 and Ser130 are represented separately, but they belong to the same molecule. Amino acid numbering is that of Ambler et al. Reprinted from C. C. H. Chen and O. Herzberg, J. Mol. Biol. 224:1103–1113, 1992, with permission from the publisher.

Citation: Mascaretti O. 2003. β-Lactam Compounds as β-Lactamase Inhibitors, p 159-170. In Bacteria versus Antibacterial Agents. ASM Press, Washington, DC. doi: 10.1128/9781555817794.ch11
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Image of Figure 11.3
Figure 11.3

Chemical structure of penicillanic acid sulfone (sulbactam).

Citation: Mascaretti O. 2003. β-Lactam Compounds as β-Lactamase Inhibitors, p 159-170. In Bacteria versus Antibacterial Agents. ASM Press, Washington, DC. doi: 10.1128/9781555817794.ch11
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Image of Figure 11.4
Figure 11.4

Proposed mechanism for the inactivation of the TEM-1 β-lactamase of E. coli by sulbactam. See the text for an explanation and the identity of X. Reprinted from J. R. Knowles, Acc. Chem. Res. 18:97–104, 1985, with permission from the publisher.

Citation: Mascaretti O. 2003. β-Lactam Compounds as β-Lactamase Inhibitors, p 159-170. In Bacteria versus Antibacterial Agents. ASM Press, Washington, DC. doi: 10.1128/9781555817794.ch11
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Image of Figure 11.5
Figure 11.5

Chemical structure of 2-β-triazolylmethyl penicillanic acid sulfone (tazobactam).

Citation: Mascaretti O. 2003. β-Lactam Compounds as β-Lactamase Inhibitors, p 159-170. In Bacteria versus Antibacterial Agents. ASM Press, Washington, DC. doi: 10.1128/9781555817794.ch11
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Image of Figure 11.6
Figure 11.6

Mechanism of inactivation of TEM-1 or PC1 β-lactamase by tazobactam. For clarity, the residues Ser70 and Ser130 are represented separately, but they belong to the same molecule. Amino acid numbering is according to Ambler et al. Reprinted from Y. Yang, K. Janota, K. Tabei, N. Huang, M. M. Siegel, Y.-I. Lin, B. A. Rasmussen, and D. M. Shlaes, J. Biol. Chem. 275:26674–26682, 2000, with permission from the publisher.

Citation: Mascaretti O. 2003. β-Lactam Compounds as β-Lactamase Inhibitors, p 159-170. In Bacteria versus Antibacterial Agents. ASM Press, Washington, DC. doi: 10.1128/9781555817794.ch11
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Image of Figure 11.7
Figure 11.7

Chemical structure of sultamicillin.

Citation: Mascaretti O. 2003. β-Lactam Compounds as β-Lactamase Inhibitors, p 159-170. In Bacteria versus Antibacterial Agents. ASM Press, Washington, DC. doi: 10.1128/9781555817794.ch11
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References

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Tables

Generic image for table
Table 11.1

Antibiotic activities and inhibition of selected β-lactamases by clavulanic acid a

Citation: Mascaretti O. 2003. β-Lactam Compounds as β-Lactamase Inhibitors, p 159-170. In Bacteria versus Antibacterial Agents. ASM Press, Washington, DC. doi: 10.1128/9781555817794.ch11
Generic image for table
Table 11.2

Activity of drug combinations against some common pathogenic bacteria a

Citation: Mascaretti O. 2003. β-Lactam Compounds as β-Lactamase Inhibitors, p 159-170. In Bacteria versus Antibacterial Agents. ASM Press, Washington, DC. doi: 10.1128/9781555817794.ch11
Generic image for table
Table 11.3

Generic and common trade names of combinations of a β-lactam antibiotic plus a β-lactamase inhibitor, the preparations available, and manufacturers in the United States a

Citation: Mascaretti O. 2003. β-Lactam Compounds as β-Lactamase Inhibitors, p 159-170. In Bacteria versus Antibacterial Agents. ASM Press, Washington, DC. doi: 10.1128/9781555817794.ch11

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