Chapter 20 : Inhibitors of the Formation of the First Peptide Bond

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The oxazolidinones are a novel chemical class of synthetic antibacterial agents that target protein synthesis in a wide spectrum of gram-positive pathogens including methicillin-resistant Staphylococcus aureus (MRSA), penicillin-resistant Streptococcus pneumoniae, and vancomycin-resistant Enterococus faecium. In 1987 the antibacterial activities of the oxazolidinones were first described by scientists at E. I. du Pont de Nemours & Co., Inc. It was demonstrated that the oxazolidinone DuP721 inhibited protein synthesis in susceptible bacteria. Oxazolidinones were abandoned for some time after these earlier studies because of their high toxicity. Oxazolidinones are potent inhibitors of bacterial protein biosynthesis. Several hypotheses regarding the mode of inhibition of protein synthesis in sensitive bacteria by oxazolidinone have been proposed. Scientists found that these oxazolidinones inhibit ribosomal peptidyltransferase activity in the simple reaction of 70S ribosomes. Then they proposed that oxazolidinones inhibit bacterial protein biosynthesis by interfering with the binding of initiation fMet-tRNA to the ribosomal peptidyltransferase P site, which is vacant only prior to the formation of the first peptide bond. Then oxazolidinones do not affect the formation of the 30S preinitiation complex but do prevent the formation of the fMet-tRNA–ribosome– mRNA ternary complex. In 2002, Auckland and coworkers reported the first three examples of resistant enterococci (two isolates of E. faecium and one of E. faecalis) isolated in the United Kingdom; they were obtained from patients who had received linezolid.

Citation: Mascaretti O. 2003. Inhibitors of the Formation of the First Peptide Bond, p 279-284. In Bacteria versus Antibacterial Agents. ASM Press, Washington, DC. doi: 10.1128/9781555817794.ch20
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Figure 20.1

Chemical structures of linezolid, XA043, and DuP721.

Citation: Mascaretti O. 2003. Inhibitors of the Formation of the First Peptide Bond, p 279-284. In Bacteria versus Antibacterial Agents. ASM Press, Washington, DC. doi: 10.1128/9781555817794.ch20
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Image of Figure 20.2
Figure 20.2

Secondary structure of the segment of E. coli 23S rRNA encompassing the central-loop domain V and the neighboring regions. E. coli linezolid resistance mutations are marked by arrows. Reprinted from L. Xiong, P. Kloss, S. Douthwaite, N. M. Anderson, S. Swaney, D. L. Shinabarger, and A. S. Mankin, J. Bacteriol. 182:5325–5331, 2000, with permission from the American Society for Microbiology.

Citation: Mascaretti O. 2003. Inhibitors of the Formation of the First Peptide Bond, p 279-284. In Bacteria versus Antibacterial Agents. ASM Press, Washington, DC. doi: 10.1128/9781555817794.ch20
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