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Chapter 9 : Inhibitors of Peptidoglycan Biosynthesis

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Abstract:

This chapter provides an overview on inhibitors of peptidoglycan biosynthesis cephalosporins. The clinical use of cephalosporin C was limited by its generally weak antibacterial activity. With the penicillins as a precedent, the 7-acylamino group was the first target for variation in the search for improved activity. The first-generation cephalosporins are used to treat Staphylococcus aureus and nonenterococcal streptococcal infections when it is necessary to avoid the use of penicillin. The second-generation cephalosporins should be considered in three groups: the true cephalosporins, the cephamycins, and the carbacephems. The first is a syn-oxime, found in cefuroxime as well as in other third- and fourth-generation cephalosporins. The effectiveness against gram-negative bacteria that is so notable in carbenicillin and ticarcillin (which is attributed to the α-COOH group on the acyl side chain) is also present in moxalactam. As in amoxicillin, the p-OH group on the benzene ring is incorporated in moxalactam to increase the level of drug in blood and to increase its half-life. The 1-methyl-tetrazolyl group at position 3, which has been useful in several third-generation cephalosporins, was also incorporated into the structure of this molecule. The first-generation cephalosporins have a spectrum that includes E. coli, K. pneumoniae, P. mirabilis, and most gram-positive cocci, although not enterococci or methicillin-resistant enterococci. The second-generation cephalosporins have broader in vitro activity against gram-negative bacteria. The third-generation cephalosporins are more active than first- and second-generation drugs against gram-negative organisms.

Citation: Mascaretti O. 2003. Inhibitors of Peptidoglycan Biosynthesis, p 139-152. In Bacteria versus Antibacterial Agents. ASM Press, Washington, DC. doi: 10.1128/9781555817794.ch9
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Figures

Image of Figure 9.1
Figure 9.1

Chemical structure of cephalosporin C.

Citation: Mascaretti O. 2003. Inhibitors of Peptidoglycan Biosynthesis, p 139-152. In Bacteria versus Antibacterial Agents. ASM Press, Washington, DC. doi: 10.1128/9781555817794.ch9
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Image of Figure 9.2
Figure 9.2

Semisynthesis of cephalosporins through the intermediate 7-ACA.

Citation: Mascaretti O. 2003. Inhibitors of Peptidoglycan Biosynthesis, p 139-152. In Bacteria versus Antibacterial Agents. ASM Press, Washington, DC. doi: 10.1128/9781555817794.ch9
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Image of Figure 9.3
Figure 9.3

Chemical conversion of the penicillin V β-sulfoxide methyl ester into 7-amino desacetylcephalosporanic acid as originally developed by Morin and coworkers at Eli Lilly Laboratories.

Citation: Mascaretti O. 2003. Inhibitors of Peptidoglycan Biosynthesis, p 139-152. In Bacteria versus Antibacterial Agents. ASM Press, Washington, DC. doi: 10.1128/9781555817794.ch9
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Image of Figure 9.4
Figure 9.4

Hydrolysis of the 3'-acetoxy group of cephalothin by serum esterases.

Citation: Mascaretti O. 2003. Inhibitors of Peptidoglycan Biosynthesis, p 139-152. In Bacteria versus Antibacterial Agents. ASM Press, Washington, DC. doi: 10.1128/9781555817794.ch9
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Image of Figure 9.5
Figure 9.5

Participation of a leaving group (X) in the opening of the β-lactam ring of cephalosporins. Nu can be the hydroxyl group of serine β-lactamases or a chemical nucleophile such as an alkoxide ion or hydroxylamine.

Citation: Mascaretti O. 2003. Inhibitors of Peptidoglycan Biosynthesis, p 139-152. In Bacteria versus Antibacterial Agents. ASM Press, Washington, DC. doi: 10.1128/9781555817794.ch9
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Image of Figure 9.6
Figure 9.6

Schematic drawing of the cephalosporinplatinum complex prodrugs for the ADEPT method. mAb, monoclonal antibody. Reprinted from S. Hanessian and J. Wang, Can. J. Chem. 71:896–906, 1993, with permission from the publisher.

Citation: Mascaretti O. 2003. Inhibitors of Peptidoglycan Biosynthesis, p 139-152. In Bacteria versus Antibacterial Agents. ASM Press, Washington, DC. doi: 10.1128/9781555817794.ch9
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Image of Figure 9.7
Figure 9.7

Structures and routes of administration of first-generation cephalosporins.

Citation: Mascaretti O. 2003. Inhibitors of Peptidoglycan Biosynthesis, p 139-152. In Bacteria versus Antibacterial Agents. ASM Press, Washington, DC. doi: 10.1128/9781555817794.ch9
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Figure 9.8

Structures and routes of administration of second-generation cephalosporins.

Citation: Mascaretti O. 2003. Inhibitors of Peptidoglycan Biosynthesis, p 139-152. In Bacteria versus Antibacterial Agents. ASM Press, Washington, DC. doi: 10.1128/9781555817794.ch9
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Figure 9.9

Structures and routes of administration of third-generation cephalosporins.

Citation: Mascaretti O. 2003. Inhibitors of Peptidoglycan Biosynthesis, p 139-152. In Bacteria versus Antibacterial Agents. ASM Press, Washington, DC. doi: 10.1128/9781555817794.ch9
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Figure 9.10

Structures and routes of administration of fourth-generation cephalosporins.

Citation: Mascaretti O. 2003. Inhibitors of Peptidoglycan Biosynthesis, p 139-152. In Bacteria versus Antibacterial Agents. ASM Press, Washington, DC. doi: 10.1128/9781555817794.ch9
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Image of Figure 9.11
Figure 9.11

Chemical structures of the chromogenic cephalosporins nitrocefin, PADAC, and CENTA.

Citation: Mascaretti O. 2003. Inhibitors of Peptidoglycan Biosynthesis, p 139-152. In Bacteria versus Antibacterial Agents. ASM Press, Washington, DC. doi: 10.1128/9781555817794.ch9
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References

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Tables

Generic image for table
Table 9.1

Classification of cephalosporins by generations

Citation: Mascaretti O. 2003. Inhibitors of Peptidoglycan Biosynthesis, p 139-152. In Bacteria versus Antibacterial Agents. ASM Press, Washington, DC. doi: 10.1128/9781555817794.ch9
Generic image for table
Table 9.2

Generic and common trade names of cephalosporins, the preparations available, and manufacturers in the United States

Citation: Mascaretti O. 2003. Inhibitors of Peptidoglycan Biosynthesis, p 139-152. In Bacteria versus Antibacterial Agents. ASM Press, Washington, DC. doi: 10.1128/9781555817794.ch9

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