Chapter 19 : An Inhibitor of the 50S Ribosomal Subunit

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.