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Chapter 3 : Antibiotics That Act on Cell Wall Biosynthesis

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Abstract:

This chapter deals with antibiotics that interdict any of the several steps in bacterial cell wall assembly, from biogenesis of the dedicated monomers to the specialized assembly, membrane translocation, and extracellular cross-linking and strengthening of the exoskeletal peptidoglycan (PG) layers. Many of the antibiotics that affect bacterial cell walls inhibit enzymes or sequester substrates involved in peptidoglycan assembly and cross-linking. Distinct features of outer membranes even among gram-negative bacteria can lead to differences in permeability to antibiotics. For example, outer membranes show about 100-fold lower permeability to cephalosporins such as cephaloridine than other gram-negative bacteria, in part because of porins with small pores to reduce inward passage of the antibiotics into the periplasmic space. Some of the transglycosylases and transpeptidases are bifunctional with discrete transglycosylase and transpeptidase domains, and members of this subset are of particular importance as killing targets of β-lactam antibiotics. The most celebrated of the antibiotics that kill bacteria by blocking the crucial transpeptidations that lead to mechanically strong PG through the covalent cross-links of peptide strands are the β-lactam antibiotics. Moenomycin has a 25-carbon lipid alcohol, moecinol, linked via a phosphoglycerate to a pentasaccharide tail in phosphodiester linkage. NMR analysis has provided a model for the three-dimensional structure with the proposal that the E and F rings of the carbohydrate moiety interact, as a substrate analog, with the target transglycosylase to shut down addition of the disaccharyl pentapeptide units in PG layer growth.

Citation: Walsh C. 2003. Antibiotics That Act on Cell Wall Biosynthesis, p 22-49. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch3

Key Concept Ranking

Antibacterial Agents
0.74839807
Fourth Generation Cephalosporins
0.5274849
Glycopeptide Antibiotics
0.51949733
0.74839807
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Antibiotics that act on cell wall biosynthesis.

Citation: Walsh C. 2003. Antibiotics That Act on Cell Wall Biosynthesis, p 22-49. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch3
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Figure 3.1

Cell wall structures of gram-positive and gram-negative bacteria: (A) differences in outer membrane permeability barriers; (B) peptidoglycan elongation by transglycosylase action; (C) peptidoglycan cross-linking by transpeptidase action; (D) penetration of antibiotics to the cytoplasmic membrane in gram-positive bacteria.

Citation: Walsh C. 2003. Antibiotics That Act on Cell Wall Biosynthesis, p 22-49. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch3
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Figure 3.2

Cell walls of bacteria. (A and B) Schematic diagrams of gram-positive (A) and gram-negative (B) cell walls. (C and D) Electron micrographs showing the cell walls of a gram-positive bacterium, (C), and a gram-negative bacterium, (D). (E and F) Scanning electron micrographs of gram-positive () (E) and gram-negative () (F) bacteria. Note the surface texture in the cells shown in panels E and F. A single cell of or is about 1 mm in diameter.

Citation: Walsh C. 2003. Antibiotics That Act on Cell Wall Biosynthesis, p 22-49. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch3
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Figure 3.3

Action of cell wall transglycosylases on the C-lipid-linked -acetyl-muramyl (MurNAc) pentapeptide substrate.

Citation: Walsh C. 2003. Antibiotics That Act on Cell Wall Biosynthesis, p 22-49. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch3
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Figure 3.4

Assembly of UDP-MurNAc pentapeptide by the six enzymes MurA-F.

Citation: Walsh C. 2003. Antibiotics That Act on Cell Wall Biosynthesis, p 22-49. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch3
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Figure 3.5

(A) Sequential action of MurA and MurB to convert UDP--acetyl-glucosamine (GlcNAc) to UDP--MurNAc. (B) Inactivation of MurA by the antibiotic fosfomycin.

Citation: Walsh C. 2003. Antibiotics That Act on Cell Wall Biosynthesis, p 22-49. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch3
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Figure 3.6

Conversion of UDP-MurNAc to UDP-MurNAc tripeptide by action of MurC, D, and E.

Citation: Walsh C. 2003. Antibiotics That Act on Cell Wall Biosynthesis, p 22-49. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch3
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Figure 3.7

(A) Aminoacyl-phosphate generation. (B) MurC example with UDP-MurNAc-P as a bound intermediate attacked by the amino group of cosubstrate l-Ala. (C) UDP-tripeptidyl acyl-P intermediate in MurF catalysis: attack by d-Ala-D-Ala.

Citation: Walsh C. 2003. Antibiotics That Act on Cell Wall Biosynthesis, p 22-49. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch3
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Figure 3.8

(A) Sequential action of alanine racemase and d-Ala-d-Ala ligase (Ddl) to generate d-Ala-d-Ala. (B) d-Ala-P intermediate in Ddl catalysis.

Citation: Walsh C. 2003. Antibiotics That Act on Cell Wall Biosynthesis, p 22-49. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch3
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Figure 3.9

(A) Enzymatic formation of the lipid I and lipid II intermediates in the membrane phase of peptidoglycan assembly. (B) Nucleoside-peptide inhibitors of MraY.

Citation: Walsh C. 2003. Antibiotics That Act on Cell Wall Biosynthesis, p 22-49. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch3
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Figure 3.10

The lipid carrier cycle in peptidoglycan assembly. TGase, transglycosylase; PPiase, pyrophosphatase.

Citation: Walsh C. 2003. Antibiotics That Act on Cell Wall Biosynthesis, p 22-49. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch3
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Figure 3.11

Structures of two antibiotics that form stoichiol metric complexes with lipid II: (A) ramoplanin; (B) mersacidin.

Citation: Walsh C. 2003. Antibiotics That Act on Cell Wall Biosynthesis, p 22-49. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch3
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Figure 3.12

Bacitracin and a model for complexation of the C lipid phosphate to block the lipid cycle.

Citation: Walsh C. 2003. Antibiotics That Act on Cell Wall Biosynthesis, p 22-49. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch3
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Figure 3.13

Schematic of a multi-enzyme complex involved in traveling along the peptidoglycan scaffold during elongation. TG, transglycosylase; TP, transpeptidase; TP/TG, Bi-functional transpeptidase / transglycosylase; EP, endopeptidase; LT, lytic transglycosylase. (Adapted from Holtje [1998], with permission.)

Citation: Walsh C. 2003. Antibiotics That Act on Cell Wall Biosynthesis, p 22-49. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch3
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Image of Figure 3.14
Figure 3.14

-Lactam antibiotics: (A) penicillins, (B) cephalosporins, (C) carbapenems, (D) monobactams, and (E) clavams.

Citation: Walsh C. 2003. Antibiotics That Act on Cell Wall Biosynthesis, p 22-49. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch3
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Figure 3.15

Mechanism of the PG transpeptidation reaction to create the DAP-d-Ala isopeptide bond: acyl enzyme intermediate in transpeptidase action. (A) Acyl enzyme formation; (B) acyl enzyme deacylation and capture by the amine nucleophile of a neighboring chain.

Citation: Walsh C. 2003. Antibiotics That Act on Cell Wall Biosynthesis, p 22-49. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch3
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Figure 3.16

Reaction of penicillin as a suicide substrate for PG transpeptidases.

Citation: Walsh C. 2003. Antibiotics That Act on Cell Wall Biosynthesis, p 22-49. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch3
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Image of Figure 3.17
Figure 3.17

Multiple penicillin-binding proteins in : auto-radiographs of 14C-penicilloylproteins of separated on denaturing gel electrophoresis. (From Dougherty et al. [1996], with permission.)

Citation: Walsh C. 2003. Antibiotics That Act on Cell Wall Biosynthesis, p 22-49. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch3
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Image of Figure 3.18a
Figure 3.18a

Different generations of (A) penicillins and (B) cephalosporins. (Adapted from Scholar and Pratt [2000], with permission.)

Citation: Walsh C. 2003. Antibiotics That Act on Cell Wall Biosynthesis, p 22-49. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch3
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Image of Figure 3.18b
Figure 3.18b

Different generations of (A) penicillins and (B) cephalosporins. (Adapted from Scholar and Pratt [2000], with permission.)

Citation: Walsh C. 2003. Antibiotics That Act on Cell Wall Biosynthesis, p 22-49. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch3
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Figure 3.19

Structures of the glycopeptide antibiotics vancomycin and teicoplanin.

Citation: Walsh C. 2003. Antibiotics That Act on Cell Wall Biosynthesis, p 22-49. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch3
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Image of Figure 3.20
Figure 3.20

Sequestration of PG-d-Ala-d-Ala termini by vancomycin. (A) Five hydrogen bonds between the antibiotic and PG terminus; (B) space-filling model of the antibiotic and PG terminus.

Citation: Walsh C. 2003. Antibiotics That Act on Cell Wall Biosynthesis, p 22-49. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch3
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Image of Figure 3.21
Figure 3.21

PG termini interacting with vancomycin and teicoplanin: (A) un-cross-linked strands on preexisting PG; (B) the lipid II substrate before polymerization into PG.

Citation: Walsh C. 2003. Antibiotics That Act on Cell Wall Biosynthesis, p 22-49. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch3
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Image of Figure 3.22
Figure 3.22

Model for moenomycin interaction with target transglycosylases. (From Kurz et al. [1998], with permission.)

Citation: Walsh C. 2003. Antibiotics That Act on Cell Wall Biosynthesis, p 22-49. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch3
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References

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Tables

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Table 3.1

Proteins covalently linked to peptidoglycan

Citation: Walsh C. 2003. Antibiotics That Act on Cell Wall Biosynthesis, p 22-49. In Antibiotics. ASM Press, Washington, DC. doi: 10.1128/9781555817886.ch3

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