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Chapter 13 : Inhibitors of Peptidoglycan Biosynthesis

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Inhibitors of Peptidoglycan Biosynthesis, Page 1 of 2

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Abstract:

The structure and biosynthesis of the peptidoglycan unit have special significance relative to the action of the antibiotics fosfomycin, D-cycloserine, and bacitracin and the glycopeptides vancomycin and teicoplanin, as well as the β-lactam antibiotics. The biosynthesis of peptidoglycan was first worked out with Staphylococcus aureus. Although bacteria show variations in peptidoglycan structure, the biosynthetic sequence in S. aureus serves to illustrate the general features of the process. The biosynthesis of peptidoglycan may be conveniently divided into stages inhibited by fosfomycin and those inhibited by D-cycloserine antibiotics. Fosfomycin acts as a phosphoenolpyruvate analogue and irreversibly inhibits the enol-pyruvyl transferase that catalyzes the transfer of phosphoenolpyruvate in the formation of UDP–N-acetylglucosamine (UDPNAG) enolpyruvate. In multiple-dose regimens, resistance to fosfomycin emerges rapidly; however, cross-resistance with other antibacterial agents has not been common. Resistance to fosfomycin occurs by three mechanisms; two of them are encoded on the chromosome, whereas the third is of plasmid origin. Fosfomycin is inactivated by the opening of its epoxide ring followed by formation of an adduct between its C-1 atom and the sulfhydryl group of the cysteine of the tripeptide glutathione. D-Cycloserine is now used only for the treatment of patients with tuberculosis whose Mycobacterium tuberculosis strains are resistant to several first-line drugs. Resistance in Mycobacterium tuberculosis is rare and develops only slowly in patients treated with D-cycloserine alone.

Citation: Mascaretti O. 2003. Inhibitors of Peptidoglycan Biosynthesis, p 199-202. In Bacteria versus Antibacterial Agents. ASM Press, Washington, DC. doi: 10.1128/9781555817794.ch13
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Figures

Image of Figure 13.1
Figure 13.1

Schematic representation of the reactions in the cytoplasm during peptidoglycan synthesis in S. aureus. The sites of inhibition by fosfomycin and -cycloserine are indicated by large arrows.

Citation: Mascaretti O. 2003. Inhibitors of Peptidoglycan Biosynthesis, p 199-202. In Bacteria versus Antibacterial Agents. ASM Press, Washington, DC. doi: 10.1128/9781555817794.ch13
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Image of Figure 13.2
Figure 13.2

Chemical structures of fosfomycin and fosfomycin tromethamine.

Citation: Mascaretti O. 2003. Inhibitors of Peptidoglycan Biosynthesis, p 199-202. In Bacteria versus Antibacterial Agents. ASM Press, Washington, DC. doi: 10.1128/9781555817794.ch13
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Image of Figure 13.3
Figure 13.3

Suggested mechanism of action of fosfomycin at the molecular level. Enz, enzyme.

Citation: Mascaretti O. 2003. Inhibitors of Peptidoglycan Biosynthesis, p 199-202. In Bacteria versus Antibacterial Agents. ASM Press, Washington, DC. doi: 10.1128/9781555817794.ch13
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Image of Figure 13.4
Figure 13.4

Mechanism of fosfomycin resistance mediated by the FosA protein.

Citation: Mascaretti O. 2003. Inhibitors of Peptidoglycan Biosynthesis, p 199-202. In Bacteria versus Antibacterial Agents. ASM Press, Washington, DC. doi: 10.1128/9781555817794.ch13
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Image of Figure 13.5
Figure 13.5

Chemical structures of -cycloserine and -alanine in the zwitterionic form.

Citation: Mascaretti O. 2003. Inhibitors of Peptidoglycan Biosynthesis, p 199-202. In Bacteria versus Antibacterial Agents. ASM Press, Washington, DC. doi: 10.1128/9781555817794.ch13
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References

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