Inhibitors of DNA-Dependent RNA Polymerase Rifamycins

Abstract

The clinically useful rifamycins include rifampin (known in some countries as rifampicin), a semisynthetic derivative of rifamycin B. Rifamycin B and structurally related antibiotics inhibit bacterial RNA synthesis by binding to the β-subunit of bacterial DNA-dependent RNA polymerases. A section of the chapter provides an overview of transcription in bacteria and the structure and function of bacterial DNA-dependent RNA polymerase. In the initiation phase of RNA synthesis on a duplex DNA template, the RNA polymerase binds at a specific site on the DNA called the promoter. Here, it unwinds and unpairs a small segment of DNA. Rifamycins are characterized by an aliphatic ansa-bridge that connects two nonadjacent positions of a naphthalenic nucleus. Rifamycin SV can be obtained by chemical modification of other rifamycins but is also produced by fermentation of some strains of A. mediterranei. The rifamycins are biologically active against gram-positive bacteria and mycobacteria, particularly Mycobacterium tuberculosis, the agent of tuberculosis. The mechanism of action of rifabutin against M. avium is unknown; in some other susceptible bacteria, this antibiotic inhibits DNA-dependent RNA polymerase. Rifapentine, like other rifamycins, inhibits DNA-dependent RNA polymerase. In addition to its activity against M. tuberculosis, it is active in vitro against M. avium and Toxoplasma gondii. Strains of M. tuberculosis resistant to rifamycin are also resistant to rifapentine. A major advantage of rifapentine over rifampin is that only twice-weekly doses of rifapentine are required for initial treatment of tuberculosis and once-weekly doses are needed during the continuation phase of treatment.