Rifamycins as inhibitors of RNA and DNA polymerases

Abstract

The rifamycins are a class of compounds obtained by chemical modification of one of the fermentation products of S t rep tomyces mediterranei (Sensi et al., 1966). This group of compounds was characterized in early reports to possess strong antimicrobial activity which led to their clinical application as antibiotics, particularly in the treatment of tuberculosis (Furesz et al., 1965). The interest of molecular biologists in these compounds was promoted by the finding of a specific anti-polymerase activity for bacterial RNA polymerase, which appears to be the mechanism by which the anti-bacterial activity is expressed. One of the compounds, rifampicin, was successfully used to elucidate steps of the complex process of RNA transcription. Although the low doses of drug required for inhibition and the stoichiometry of binding are indicative of specificity of the interaction of this complex molecule with the bacterial enzyme, other targets appear to be reached by the drug when high concentrations are used. For example, effects on mitochondrial RNA polymerase from N e u r o s p o r a crassa (Kuntzel and Schafer, 1971), on RNA synthesis in heart mitochondria (Gamble and McCluer, 1970), and on the multiplication of vaccinia virus (see Riva and Silvestri, 1972, for a review) have been reported, suggesting that a broader range of action involving polymerases from different sources might be inherent to this class of compounds. It seemed reasonable to assume that the limited effectiveness of rifampicin for polymerases from sources other than bacteria could be overcome by modification of the drug molecule. With this in mind, rifampicin and a few of its analogs were used as inhibitors of the RNA-dependent DNA polymerase of RNA tumor viruses at a time when the discovery of this enzyme was being utilized in studies designed to obtain an understanding of the mechanism of cell transformation and as a tool to explore the possible link between viruses and human cancer. In this article, the outcome of these studies, which indicated a common antipolymerase activity of rifamycin compounds, will be presented. An updated outline of the studies of rifampicin with the bacterial RNA polymerase, the subject of previous review articles (Wehrli and Staehelin, 1970; Riva and Silvestri, 1972), will be presented for parallel comparisons with the studies on the interaction of rifamycins with the viral reverse transcriptase and with eucaryotic RNA polymerases.