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Ansamycin

Page history last edited by PBworks 12 years, 6 months ago

History

Ansamycins is a family of secondary metabolites that show antimicrobial activity against many gram-positive and some gram-negative bacteria[1] and includes various compounds among which: streptovaricins and rifamycins.  In addition, these compounds demonstrated antiviral activity towards bacteriophages and poxviruses.  They are named ansamycins—ansa from the Latin for handle—because of their unique structure which comprises of an aromatic moiety bridged by an aliphatic chain.[2]  The main difference between various derivatives of ansamycins is the aromatic moiety, which can be a naphthalene ring or a naphthoquinone ring as in rifamycin and naphthomycin (Fig. 1).[3] 

 

 

Rifamycin Examples

 

Another variation comprises of benzene or a benzoquinone ring system as in geldanamycin or ansamitocin.  Ansamycins were first discovered in 1959 by Sensi et al from Amycolatopsis mediterranei, an Actinomycete.[4]  Rifamycins are a subclass of ansamycins with high potency against mycobacterial activity.  This resulted in their wide use in the treatment of tuberculosis, leprosy, and AIDS-related mycobacterial infections.[5]  Since then various analogues have been isolated from other prokaryotes.

 

Mechanism of Action

            The biological activity of rifamycins relies on the inhibition of DNA-dependent RNA synthesis.[6]  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.[7]  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.[8]

 

Biosynthesis

            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.[9]  AHBA is believed to have originated from the Shikimate pathway, however this was not incorporated into the biosynthetic mechanism (Fig. 2)[7]  This is due to the observation that 3 amino-acid analogues converted into AHBA in cell-free extracts of A. mediterranei.[7]

 

 

            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.[11]  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.[7]  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 (Fig. 3).

 

 

 

 

 

 

 

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.[12]  In addition, rifabutin and rifapentine have both been used against tuberculosis acquired in HIV-positive patients. 

 





[1] Wehrli, W.; Staehelin, M. Bacteriol. Rev. 1971, 35, 290.

[2] Prelog, V.; Oppolzer, W. Helv. Chim. Acta 1973, 56, 2279.

[3] Balerna, M.; Keller-Schierlein, W.; Martius, C.; Wolf, H.; Zähner, H. Arch. Mikrobiol. 1969, 65, 303.

[4] Sensi, P.; Margalith, P.; Timbal, M. T. Farmaco, Ed. Sci. 1959, 14, 146.

[5] Floss, H. G.; Yu, T.  Curr. Opin. Chem. Biol. 1999, 3, 592-7.

[6] Calvori, C.; Frontali, L.; Leoni, L.; Tecce, G. Nature 1965, 207, 417.

[7]  Floss, H.G.; Yu, T.  Chem. Rev. 2005, 105, 621.

[8] Lancini, G.; Cavalleri, B. In Biotechnology of Antibiotics; Strohl, W. R., Ed.; Marcel Dekker: New York, 1997; p 521.

[9] Lancini G, Cavallieri B: Rifamycins. In Biotechnology of Antibiotics, edn 2. Edited by Strohl WR. New York: Dekker; 1997:521-549.

[10] Yu, T.-W.; Müller, R.; Müller, M.; Zhang, H.; Draeger, G.; Kim, C.-G.; Leistner, E.; Floss, H. G. J. Biol. Chem. 2001, 276, 12546.

[11] Arakawa, K.; Müller, R.; Mahmud, T.; Yu, T.-W.; Floss, H. G. J. Am. Chem. Soc. 2002, 124, 10644.

[12] Pozniak, A. L.; Miller, R.; Ormerod, L. P. AIDS  1999, 13, 435.

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