8 Antibiotics and the RNA World: A Role for Low-molecular-weight Effectors in Biochemical Evolution?

Abstract

There is much more to molecular and cell biology than DNA, RNA, and proteins! A very large number of secondary metabolites produced by microbes and plants have been identified; these natural products include some of the most potent inhibitors of cellular metabolic reactions. The best-known inhibitors are antibiotics, used in the therapy of infectious disease, which have a number of cellular targets. Not surprisingly, antibiotics may interact with different macromolecules to inhibit cellular processes.

The protein synthesis inhibitors have been studied for many years, beginning with the pioneering work of the laboratory of E.F. Gale in Cambridge on the inhibition of bacterial cells, which could be interpreted as translation inhibition. The development of cell-free polypeptide synthesis in the early 1960s permitted the testing of many putative protein synthesis inhibitors. Probably the first conclusive experiments to focus on cellular targets for translation inhibitors were those of Erdös and Ullmann (1959) with streptomycin. Subsequently, the use of fractionated cell-free extracts with separated ribosomal subunits allowed the identification of many antibiotics as specific inhibitors of ribosome function. Within a few years, the mechanism of action of most inhibitors of translation had been worked out in general terms, although not in any great detail at the chemical level. An important concept, first elaborated by Vazquez (1964), was the species specificity of the interaction between inhibitors of protein synthesis and their targets (for an excellent review, see Cundliffe 1981). The narrow range of activity of many of these compounds is well known and is critical...