Inhibition of RNA Polymerase by Rifampicin and Rifamycin-Like Molecules.

RNA polymerases (RNAPs) accomplish the first step of gene expression in all living organisms. However, the sequence divergence between bacterial and human RNAPs makes the bacterial RNAP a promising target for antibiotic development. The most clinically important and extensively studied class of antibiotics known to inhibit bacterial RNAP are the rifamycins. For example, rifamycins are a vital element of the current combination therapy for treatment of tuberculosis. Here, we provide an overview of the history of the discovery of rifamycins, their mechanisms of action, the mechanisms of bacterial resistance against them, and progress in their further development.

From milk to rifampicin and back again: history of failures and successes in the treatment for tuberculosis.

The millennial flight against tuberculosis has been characterized by several defeats. Roman physicians suggested to consumptives better nutrition, sea voyages and change of air, while, during the Middle Ages, 'royal touch' were considered as an effective remedy for scrofula. In the following centuries, phthisis was cured using old herbal preparations and new chemical compounds, mainly aimed at soothing symptoms; in addition, harmful approaches (for example, bleeding and purging) were commonly accepted, according to medical theories of that time. In the second part of the nineteenth century, the discovery of the contagious nature of consumption (Villemin, Koch) addressed physicians and scientists toward often-unsuccessful remedies, such as antiparasitic treatment, immunomodulants, vaccination and serum therapy. In that period only sanatorium regimen--based on aerotherapy, bed rest, better nutrition, sunbathing and moderate physical exercise--appeared to provide first partial successes. In these structures, more invasive approaches were also employed, such as lung collapse surgical interventions (for example, phrenicotomy, thoracoplasty) and artificial pneumothorax. Since the second part of the twentieth century, the industrialization of pharmacotherapy, the development of antimicrobial chemotherapy and the introduction of new antibiotics (streptomycin, isoniazid, para-aminosalicylic acid, ethambutol and pyrazinamide) deeply revolutionized treatment for tuberculosis, allowing to achieve important successes. In this same period, the figure of Piero Sensi (1920-2013) deserves to be recalled for his contribution in the development of rifampicin that played a decisive role in the chemical fight against the white plague. Nowadays, antibiotic resistance is an emerging problem, representing a new challenge for physicians and scientists who sometimes re-proposed old 'historical' approaches.