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Chapter 19 : An Inhibitor of the 50S Ribosomal Subunit

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An Inhibitor of the 50S Ribosomal Subunit, Page 1 of 2

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Abstract:

Chloramphenicol was the first orally active broad-spectrum antibiotic to be discovered. A valuable property of chloramphenicol is that it readily crosses the blood-brain barrier and can therefore be used to treat infections of the central nervous system caused by susceptible organisms. The aplasia is not dose related and can become manifest weeks to months after the use of chloramphenicol. Chloramphenicol is therefore reserved for situations where the benefits exceed the risk. Chloramphenicol is known to bind at the peptidyltransferase center of the large ribosomal subunit. To elucidate the structural basis of ribosome-chloramphenicol interactions, scientists have determined the high-resolution X-ray structure of the 50S ribosomal subunit of the eubacterium Deinococcus radiodurans in complex with chloramphenicol. The most clinically important mechanism of resistance in bacteria is that of O acetylation catalyzed by the enzyme chloramphenicol O-acetyltransferase (CAT). This chapter discusses the postulated general mechanism for the CAT-catalyzed acetylation of chloramphenicol. Although the CAT mechanism for resistance to chloramphenicol is widespread in bacteria, it is not used by the chloramphenicol-producing Streptomyces strains to protect themselves against their own toxic product. However, a 3-O phosphoester of chloramphenicol was identified in Streptomyces venezuelae, suggesting that the producing organism has a mechanism of chloramphenicol resistance that has not been encountered in other microbial systems. Researchers reported their studies on active efflux of chloramphenicol in susceptible E. coli strains and in multiple-antibiotic-resistant (Mar) mutants; the mechanism was shown to depend on proton motive force.

Citation: Mascaretti O. 2003. An Inhibitor of the 50S Ribosomal Subunit, p 273-278. In Bacteria versus Antibacterial Agents. ASM Press, Washington, DC. doi: 10.1128/9781555817794.ch19
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Figures

Image of Figure 19.1
Figure 19.1

Chemical structures of chloramphenicol, chloramphenicol palmitate, and chloramphenicol hemisuccinate.

Citation: Mascaretti O. 2003. An Inhibitor of the 50S Ribosomal Subunit, p 273-278. In Bacteria versus Antibacterial Agents. ASM Press, Washington, DC. doi: 10.1128/9781555817794.ch19
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Image of Figure 19.2
Figure 19.2

Interactions of chloramphenicol with the peptidyltransferase cavity. (a) Chemical structure diagram of chloramphenicol showing the interactions (arrows) of its reactive groups with the nucleotides of the peptidyltransferase cavity. Arrows between two chemical moieties indicate that the two groups are less than 4.4 Å apart. (b) Secondary structure of the peptidyltransferase ring of Deinococcus radiodurans, showing the nucleotides involved in the interaction with chloramphenicol. Reprinted from F. Schlünzen, R. Zarivach, J. Harms, A. Bashan, A. Tocilj, R. Albrecht, A. Yonath, and F. Franceschi, Nature 413:814–821, 1999, with permission from the publisher.

Citation: Mascaretti O. 2003. An Inhibitor of the 50S Ribosomal Subunit, p 273-278. In Bacteria versus Antibacterial Agents. ASM Press, Washington, DC. doi: 10.1128/9781555817794.ch19
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Image of Figure 19.3
Figure 19.3

CAT-catalyzed acetylation of chloramphenicol and 1-Oacetylchloramphenicol, yielding 1,3-di-O-acetylchloramphenicol as the final product.

Citation: Mascaretti O. 2003. An Inhibitor of the 50S Ribosomal Subunit, p 273-278. In Bacteria versus Antibacterial Agents. ASM Press, Washington, DC. doi: 10.1128/9781555817794.ch19
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Image of Figure 19.4
Figure 19.4

Mechanism postulated for the inactivation of chloramphenicol catalyzed by CAT with the cofactor acetyl-CoA.

Citation: Mascaretti O. 2003. An Inhibitor of the 50S Ribosomal Subunit, p 273-278. In Bacteria versus Antibacterial Agents. ASM Press, Washington, DC. doi: 10.1128/9781555817794.ch19
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References

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1. Nagabhushan, T.,, G. H. Miller,, and K. J. Varma,. 1993. Chloramphenicol and analogues, p. 175192. In M. Howe-Grant (ed.), Chemotherapeutics and Disease Control. John Wiley & Sons, Inc., New York, N.Y.
2. Schlünzen, F.,, R. Zarivach,, J. Harms,, A. Bashan,, A. Tocilj,, R. Albrecht,, A. Yonath,, and F. Franceschi. 2001. Structural basis for the interaction of antibiotics with the peptidyl transferase centre in eubacteria. Nature 413:814821.
3. Reese, R. E.,, R. F. Betts,, and B. Gumustop. 2000. Handbook of Antibiotics, p. 441445. Lippincott Williams & Wilkins, Philadelphia, Pa.
4. Leslie, A.G.W. 1990. Refined crystal structure of chloramphenicol acetyltransferase at 1.75 Å resolution. J. Mol. Biol. 213:167186.
5. Leslie, A. G. W.,, P. C. E. Moody,, and W. V. Shaw. 1988. Structure of chloramphenicol acetyltransferase at 1.75 Å resolution. Proc. Natl. Acad. Sci. USA 85:41334177.
6. Murray, I. A.,, and W. V. Shaw. 1997. O-Acetyltransferases for chloramphenicol and other natural products. Antimicrob. Agents Chemother. 41:16.
7. Izard, T.,,and J. Ellis. 2000. The crystal structures of chloramphenicol phosphotransferase reveal a novel inactivaction mechanism. EMBO J. 19:26902700.
8. McMurry, L. M.,, A. M. George,, and S. B. Levy. 1994. Active efflux of chloramphenicol in susceptible Escherichia coli strains and in multiple-antibiotic-resistant (Mar) mutants. Antimicrob. Agents Chemother. 38:542546.

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