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Complex Interactions of Antibiotics with the Ribosome

Bernard D. Davis, Phang-Cheng Tai, Brian J. Wallace


The search for antibiotics has yielded not only many life-saving drugs, but also an even larger number of valuable reagents for the study of cell physiology. The specificity and variety of their inhibitory actions have reaffirmed Claude Bernard’s dictum: “Poisons are delicate instruments that dissect vital units”; and the ribosome has turned out to be the vital unit most frequently affected.

Antibiotics have contributed to our knowledge of the ribosome both through study of their mode of action and through their use in the isolation of mutants with altered ribosomes. However we shall not review the latter literature, except to note a particularly ingenious recent use of heterozygotes carrying multiple mutations to resistance: the polarity effects in these strains showed that the genes for several ribosomal proteins (and for factor EF-G) are linked in a single operon (Nomura and Engbaek 1972). It might also be noted that in studies of eukaryotic cells the selective action of cycloheximide on cytoplasmic ribosomes, and that of chloramphenicol on mitochondrial ribosomes, has been indispensable for recognizing that the latter make only a fraction of the mitochondrial proteins (Ashwell and Work 1970).

The early studies of protein synthesis with synthetic messengers revealed the microcycle of chain elongation but not the macrocycle of initiation and release. Hence the first anti-ribosomal antibiotics to be understood were those that can act on elongating ribosomes. Many others yielded equivocal results until the availability of a natural messenger, viral RNA, made it possible to detect specific interactions with initiating...

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