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The rifamycins are a group of antibiotics which are synthesized either naturally by the bacterium Amycolatopsis mediterranei, or artificially. They are a subclass of the larger family, Ansamycin. Rifamycins are particularly effective against mycobacteria, and are therefore used to treat tuberculosis, leprosy, and mycobacterium avium complex (MAC) infections.

The rifamycin group includes the "classic" rifamycin drugs as well as the rifamycin derivatives Rifampicin, Rifabutin and Rifapentine.



Streptomyces mediterranei was first isolated in 1957 from a soil sample collected near the beachside town of St Raphael in southern France. The name was originally given by two microbiologists working with the Italian drug company Group Lepetit SpA in Milan, the Italian Grazia Beretta and Pinhas Margalith of Israel.

In 1969 the bacterium was renamed Nocardia mediterranei when another scientist named Thiemann found that it had a cell wall typical of the Nocardia species. Then in 1986 the bacterium was renamed again as Amycolatopsis mediterranei, as the first species of a new genus, because a scientist named Lechevalier discovered that the cell wall lacked mycolic acid and was not able to be infected by the Nocardia and Rhodococcus phages.

First drugs

Rifamycins were first isolated in 1957 from a fermentation culture of Streptomyces mediterranei at the laboratory of Gruppo Lepetit SpA in Milan by a scientist named Piero Sensi, working with the Israeli scientist Pinhas Margalith. Eventually around seven rifamycins were discovered, named Rifamycin A, B, C, D, E, S and SV.

Of the various rifamycins Rifamycin B was first introduced commercially. Lepetit filed for patent protection of Rifamycin B in the UK in August 1958 and in the US in March 1959. The British patent GB921045 was granted in March 1963 and U.S. Patent 3,150,046 was granted in September 1964. The drug is widely regarded as having helped conquer the issue of drug-resistant tuberculosis in the 1960s.

Clinical Trials

Rifamycins have been used for the treatment of many diseases, most importantly HIV-related Tuberculosis. Due to the large number of available analogues and derivatives, rifamycins have been widely utilized in the elimination of pathogenic bacteria that have become resistant to commonly used antibiotics. For instance, Rifampicin is known for its potent effect and ability to prevent drug resistance. It rapidly kills fast-dividing bacilli strains as well as “persisters” cells, which remain biologically inactive for long periods of time that allow them to evade antibiotic activity [1]. In addition, rifabutin and rifapentine have both been used against tuberculosis acquired in HIV-positive patients.

Mechanism of Action

The biological activity of rifamycins relies on the inhibition of DNA-dependent RNA synthesis [2]. This is due to the high affinity of rifamycins to prokaryotic RNA polymerase. Crystal structure data of the antibiotic bound to RNA polymerase indicates that rifamycin blocks synthesis by causing strong steric clashes with the growing oligonucleotide. If rifamycin binds the polymerase after the chain elongation process has started, no effect is observed on the biosynthesis, which is consistent with a model that suggests rifamycin physically blocks the chain elongation [3]. In addition, rifamycins showed potency towards tumors. This is due to their inhibition of the enzyme reverse transcriptase, which is essential for tumor persistence. However, rifamycins potency proved to be mild and this never lead to their introduction to clinical trials.


Despite the fact that Rifamycin B is a mild antibacterial compound, it is known to be the precursor of various other clinically-utilized potent derivatives. The general scheme of biosynthesis starts with the uncommon starting unit, 3-amino-5-dihydroxybenzoic acid (AHBA), via type I polyketide pathway (PKS I) in which chain extension is performed using 2 acetate and 8 propionate units [4]. AHBA is believed to have originated from the Shikimate pathway, however this was not incorporated into the biosynthetic mechanism. This is due to the observation that 3 amino-acid analogues converted into AHBA in cell-free extracts of A. mediterranei. [5].

The rif cluster is responsible for the biosynthesis of rifamycins. It contains genes rifG through rifN, which were shown to biosynthesize AHBA.[10] RifK, rifL, rifM,and rifN are believed to act as transaminases in order to form the AHBA precursor kanosamine [6]. RifA through rifE encode a type I polyketide synthase module, with the loading module being a non-ribosomal peptide synthase. In all, rifA-E assemble a linear undecaketide and are followed by rifF, which encodes an amide synthase and causes the undecaketide to release and form a macrolactam structure. Moreover, the rif cluster contains various regulatory proteins and glycosilating genes that appear to be silent. Other types of genes seem to perform post-synthase modifications of the original polyketide.


Lepetit introduced Rifampicin, an orally active rifamycin, around 1966. Rifabutin, a derivative of rifamycin S, was invented around 1975 and came on to the US market in 1993. Hoechst Marion Roussel (now part of Aventis) introduced rifapentine in 1999.

Rifaximin is an oral rifamycin marketed in the US by Salix Pharmaceuticals that is not absorbed from the intestine. It is intended to treat intestinal infections due to Escherichia coli.

Currently available rifamycins


  • Sensi. et al., Farmaco Ed. Sci. (1959) 14, 146-147 - the paper announcing the discovery of the rifamycins.
  • Thieman et al. Arch. Microbiol. (1969), 67 147-151 - the paper which renamed Streptomyces mediterranei as Nocardia mediterranei.
  • Lechevalier et al., Int. J. Syst. Bacteriol. (1986), 36, 29) - the paper which renamed Nocardia mediterranei as Amycolatopsis mediterranei.
  1. ^ Pozniak, A. L.; Miller, R. (1999). "The treatment of tuberculosis in HIV-infected persons". AIDS 13: 435.
  2. ^ Calvori, C.; Frontali, L.; Leoni, L.; Tecce, G. (1965). "Effect of rifamycin on protein synthesis". Nature 207: 417.
  3. ^ Floss, H.G.; Yu, T. (2005). "Rifamycin-Mode of Action, Resistance, and Biosynthesis". Chem. Rev. 105: 621.
  4. ^ Lancini, G.; Cavalleri, B. (1997). In Biotechnology of Antibiotics, 521. 
  5. ^ Floss, H.G.; Yu, T. (2005). "Rifamycin-Mode of Action, Resistance, and Biosynthesis". Chem. Rev. 105: 621.
  6. ^ Arakawa, K.; Müller, R.; Mahmud, T.; Yu, T.-W.; Floss, H. G. (2002). "Characterization of the Early Stage Aminoshikimate Pathway in the Formation of 3-Amino-5-hydroxybenzoic Acid: The RifN Protein Specifically Converts Kanosamine into Kanosamine 6-Phosphate". J. Am. Chem. Soc. 124: 10644.
This article is licensed under the GNU Free Documentation License. It uses material from the Wikipedia article "Rifamycin". A list of authors is available in Wikipedia.
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