A derivative of rifamycin SV inhibiting rifampicin-resistant RNA polymerase of Escherichia coli

Abstract

The antibiotic rifampicin, a semi-synthetic derivative of rifamycin SV, inhibits bacterial RNA polymerase by forming a very stable complex with the enzyme in a 1: 1 ratio [ 11. In the search for rifamycins which would affect rifampicin-resistant bacteria, a large number of derivatives with bulky lipophilic side-chains were synthesized. Many of them proved capable of inhibiting the RNA polymerase of rifampicin-resistant E.coli mutants [2] and a number of other enzymes responsible for the polymerization of nucleotides [3]. However, the mechanism of action of these compounds against rifampicin-resistant RNA polymerases is different from the mechanism whereby rifampicin acts on the normal RNA polymerase. For example, the beststudied of these rifamycin derivatives, AF/013, unlike rifampicin prevents the binding of RNA polymerase to DNA [2,4]. The first rifamycin derivatives inhibiting a rifampicin-resistant Escherichia coli RNA polymerase by a similar mechanism to the action of rifampicin on a sensitive RNA polymerase were found among the dimeric rifamycins [5]. We have synthesized a number of derivatives of rifamycin SV with various substitutions in the 3rd position of the naphthoquinone nucleus; some of them proved capable of inhibiting rifampicin-resistant RNA polymerase of E.coli mutants. This paper describes a derivative of rifamycin SV, 3-(6-bromo-4-phenyl-2-hydrazonomethyl-quinazoline)-rifamycin SV (fig. 1) which Antibiotic resistance RM41 DNA-binding