Inhibitors of the Transcribing Enzymes

The enzymes which transcribe DNA synthesizing RNA (DNA-dependent RNA polymerases) have structural differences in eukaryotic and prokaryotic cells, as indicated by the fact, among others, that there are substances which inhibit their function selectively in prokaryotic cells (streptolydigin and the ansa antibiotics, such as rifamycins and streptovaricin) and in eukaryotic cells (-amanitin). Ansa antibiotics inhibit the initiation of RNA synthesis, whereas streptolydigin interferes with RNA elongation. Among ansa antibiotics, rifamycins have been studied more extensively, in order to obtain semisynthetic derivatives which, besides a comparable in vitro activity, showed better pharmacokinetic properties in vivo. Rifampicin, 3-(4-methylpiperazinoiminomethyl) rifamycin SV, has been selected for the oral treatment of various bacterial infections. Furthermore, a series of correlations between structure and activity have been derived, leading to the recognition of the essential structural requirements of the rifamycin molecule for penetrating into the bacterial cell and for inhibiting the enzyme. Further chemical modificatiqns have been performed, with the aim of overcoming the emergence of resistance in bacteria. Members of the streptovaricin complex and some semisynthetic rifamycins have also been found to inhibit the RNA-dependent DNA polyrnerase (reverse transcriptase) of oncogenic RNA viruses. Their selectivity of action against the reverse transcriptase in respect to the polymerases of normal cells has yet to be established. INTRODUCTION Chemotherapeutic agents used in the treatment of infectious diseases possess, as a necessary but not sufficient requisite, a selective toxicity against pathogens. Therefore, they must act on specific targets which are present in the parasite but are either absent in the host or sufficiently different to be discriminable in the two organisms. In some cases, selective toxicity depends on the fact that the chemotheraieutic agent can reach the specific target in the microorganism but not in the host cell because of a selective permeability. The search for chemotherapeutic agents has generally proceeded in an empirical way, namely, by means of a massive screening of products obtained by chemical synthesis or from natural sources, such as antibiotics, and through comparative tests of toxicity on the microorganism and host. So far this empirical approach has produced a series of useful chemotherapeutic agents that nowadays permit a successful control of most infectious diseases. Notwithstanding such successes, the necessity persists of carrying on the search for new chemotherapeutic agents with higher selectivity of action,