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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2012/11/07 10:43:25」(JST)

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The rifamycins are a group of antibiotics that 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 (or rifampin), rifabutin, rifapentine and rifalazil.

Bacterium

Streptomyces mediterranei was first isolated in 1957 from a soil sample collected near the beach-side 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.^[1]

In 1969, the bacterium was renamed Nocardia mediterranei when another scientist named Thiemann found that it has a cell wall typical of the Nocardia species. Then, in 1986, the bacterium was renamed again Amycolatopsis mediterranei, as the first species of a new genus, because a scientist named Lechevalier discovered that the cell wall lacks mycolic acid and is not able to be infected by the Nocardia and Rhodococcus phages. Based on 16S rRNA sequences, Bala et al. renamed the species in 2004 Amycolatopsis rifamycinica.

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 two scientist named Piero Sensi and Maria Teresa Timbal, 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 the 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, the most important one being 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.^[2] In addition, rifabutin and rifapentine have both been used against tuberculosis acquired in HIV-positive patients.

In addition, rifamycins showed potency towards HIV. This is due to their inhibition of the enzyme reverse transcriptase, which is essential for virulence persistence. However, rifamycin's potency proved to be mild, and this never lead to their introduction to clinical trials.

Mechanism of action

The antibacterial activity of rifamycins relies on the inhibition of bacterial DNA-dependent RNA synthesis.^[3] 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 ("steric-occlusion" mechanism).^[4]^[5] If rifamycin binds the polymerase after the chain extension process has started, no inhibition is observed on the biosynthesis, consistent with a steric-occlusion mechanism.

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.^[6] 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.^[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.^[8]^[9] "RifH" encodes aminoDAHP synthase that catalyzes the condensation between 1-deoxy-1-imino-d-erythrose 4-phosphate and phosphoenolpyruvate.^[10] 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 glycosylating genes that appear to be silent. Other types of genes seem to perform post-synthase modifications of the original polyketide.

Derivatives

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 poorly absorbed from the intestine. It has been used to treat hepatic encephalopathy and traveler's diarrhea.

Currently available rifamycins

Rifampicin or Rifampin
Rifabutin
Rifapentine
Rifaximin

References

^ Margalith P, Beretta G (1960). "Rifomycin. XI. Taxonomic study on Streptomyces mediterranei nov. sp". Mycopathol Mycol Appl 8 (4): 321–30.
^ Pozniak, A. L.; Miller, R. (1999). "The treatment of tuberculosis in HIV-infected persons". AIDS 13 (4): 435–45. doi:10.1097/00002030-199907300-00035. PMID 10197371.
^ Calvori, C.; Frontali, L.; Leoni, L.; Tecce, G. (1965). "Effect of rifamycin on protein synthesis". Nature 207 (995): 417–8. doi:10.1038/207417a0. PMID 4957347.
^ Campbell, E.A., Korzheva, N., Mustaev, A., Murakami, K., Nair, S., Goldfarb, A., Darst, S.A. (2001). "Structural mechanism for rifampicin inhibition of bacterial RNA polymerase". Cell 104 (6): 901–12. doi:10.1016/S0092-8674(01)00286-0. PMID 11290327.
^ Feklistov, A., Mekler, V., Jiang, Q., Westblade, L.F., Irschik, H., Jansen, R., Mustaev, A., Darst, S.A., Ebright, R.H. (2008). "Rifamycins do not function by allosteric modulation of binding of Mg2+ to the RNA polymerase active center". Proc Natl Acad Sci USA 105 (39): 14820–5. doi:10.1073/pnas.0802822105. PMID 18787125.
^ Lancini, G.; Cavalleri, B. (1997). In Biotechnology of Antibiotics. Marcel Dekker, New York, USA. p. 521.
^ Floss, H.G.; Yu, T. (2005). "Rifamycin-Mode of Action, Resistance, and Biosynthesis". Chem. Rev. 105 (2): 621–32. doi:10.1021/cr030112j. PMID 15700959.
^ Guo, J.; Frost, J.W. (2002). "Kanosamine Biosynthesis: A Likely Source of the Aminoshikimate Pathway's Nitrogen Atom". J. Am. Chem. Soc. 124 (36): 10642–3. doi:10.1021/ja026628m. PMID 12207504.
^ 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 (36): 10644–5. doi:10.1021/ja0206339. PMID 12207505.
^ Guo, J.; Frost, J.W. (2002). "Biosynthesis of 1-Deoxy-1-imino-d-erythrose 4-Phosphate: A Defining Metabolite in the Aminoshikimate Pathway". J. Am. Chem. Soc. 124 (4): 528–9. doi:10.1021/ja016963v. PMID 11804477.

Bibliography

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.
Bala "et al." Int J Syst Evol Microbiol 54 (2004)1145-1149; DOI 10.1099/ijs.0.02901-0, Reclassification of "Amycolatopsis mediterranei" DSM 46095 as "Amycolatopsis rifamycinica" sp. nov. - the paper with the latest name change

External links

U.S. Patent 3,150,046 for Rifamycin B.

UpToDate Contents

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1. リファマイシン（リファンピン、リファブチン、リファペンチン） rifamycins rifampin rifabutin rifapentine
2. 旅行者下痢症：臨床症状、診断、および治療 travelers diarrhea clinical manifestations diagnosis and treatment
3. 実質臓器移植候補者およびレシピエントにおける結核 tuberculosis in solid organ transplant candidates and recipients
4. Treatment of pulmonary tuberculosis in HIV-infected adults
5. 抗結核剤を使用しているHIV感染患者のモニタリング monitoring the hiv infected patient on antituberculous medications

English Journal

Comparison of substrate specificity among human arylacetamide deacetylase and carboxylesterases.

Fukami T1, Kariya M2, Kurokawa T2, Iida A2, Nakajima M2.
European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.Eur J Pharm Sci.2015 Oct 12;78:47-53. doi: 10.1016/j.ejps.2015.07.006. Epub 2015 Jul 8.
Human arylacetamide deacetylase (AADAC) is an esterase responsible for the hydrolysis of some drugs, including flutamide, indiplon, phenacetin, and rifamycins. AADAC is highly expressed in the human liver, where carboxylesterase (CES) enzymes, namely, CES1 and CES2, are also expressed. It is general
PMID 26164127

Development of a sensitive and rapid method for rifampicin impurity analysis using supercritical fluid chromatography.

Li W1, Wang J2, Yan ZY3.
Journal of pharmaceutical and biomedical analysis.J Pharm Biomed Anal.2015 Oct 10;114:341-7. doi: 10.1016/j.jpba.2015.06.012. Epub 2015 Jun 15.
A novel simple, fast and efficient supercritical fluid chromatography (SFC) method was developed and compared with RPLC method for the separation and determination of impurities in rifampicin. The separation was performed using a packed diol column and a mobile phase B (modifier) consisting of metha
PMID 26103526

The effect of complexation of 3-formylrifamycin SV macrocyclic ether derivatives with metal cations and small nitrogen-containing organic molecules on antibacterial activity against S. aureus and S. epidermidis.

Przybylski P1, Pyta K2, Czerwonka D2, Kubicka MM3, Gajecka M4.
Bioorganic & medicinal chemistry letters.Bioorg Med Chem Lett.2015 Sep 15;25(18):3903-9. doi: 10.1016/j.bmcl.2015.07.043. Epub 2015 Jul 22.
Spectroscopic studies of ether rifamycins (1-9) have shown that all these compounds tend to be zwitterions with different localizations of intramolecularly transferred proton, which influences their solubility and logP values. According to ESI MS studies, rifamycins 3 and 4 form complexes with Li(+)
PMID 26254943

Japanese Journal

The biosynthesis of 3-amino-5-hydroxybenzoic acid (AHBA), the precursor of mC_7N units in ansamycin and mitomycin antibiotics : a review

FLOSS Heinz G,YU Tin-Wein,ARAKAWA Kenji
Journal of antibiotics 64(1), 35-44, 2011-01-25
NAID 10030637355

CLINICAL USE OF RIFABUTIN, A RIFAMYCIN-CLASS ANTIBIOTIC, FOR THE TREATMENT OF TUBERCULOSIS : A supplement to the 2008 revision of "Standards for tuberculosis care"

SHIGETOU Eriko,KOHNO Shigeru
結核 86(1), 43, 2011-01-15
NAID 10029058101

Salinisporamycin, a novel metabolite from Salinispora arenicola

MATSUDA Satoru,ADACHI Kyoko,MATSUO Yoshihide,NUKINA Manabu,SHIZURI Yoshikazu
Journal of antibiotics 62(9), 519-526, 2009-09-25
NAID 10030636368

Related Pictures

★リンクテーブル★

リンク元	「リファキシミン」「リファマイシン」

「リファキシミン」

　　[★]

英: rifaximin

非吸収性抗生物質;過敏性腸症候群治療
Rifaximin is a semisynthetic, rifamycin-based non-systemic antibiotic, meaning that very little of the drug will pass the gastrointestinal wall into the circulation as is common for other types of orally administered antibiotics. It is used in the treatment of traveler's diarrhea and hepatic encephalopathy, for which it received orphan drug status from the U.S. Food and Drug Administration in 1998.(wikipedia en)

参考

http://en.wikipedia.org/wiki/Rifaximin#cite_ref-0

http://www.drugs.com/mtm/rifaximin.html

https://members.kaiserpermanente.org/kpweb/drugency/drugdetails.do?drugID=561118

http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/GastrointestinalDrugsAdvisoryCommittee/UCM201081.pdf

「リファマイシン」

　　[★]

英: rifamycin
ラ: rifamycinum
関: rifabutin rifampin rifapentine; リファマイシン系抗菌薬

[1] Margalith P, Beretta G (1960). "Rifomycin. XI. Taxonomic study on Streptomyces mediterranei nov. sp". Mycopathol Mycol Appl 8 (4): 321–30.

[2] Pozniak, A. L.; Miller, R. (1999). "The treatment of tuberculosis in HIV-infected persons". AIDS 13 (4): 435–45. doi:10.1097/00002030-199907300-00035. PMID 10197371.

[3] Calvori, C.; Frontali, L.; Leoni, L.; Tecce, G. (1965). "Effect of rifamycin on protein synthesis". Nature 207 (995): 417–8. doi:10.1038/207417a0. PMID 4957347.

[Campbell-4] Campbell, E.A., Korzheva, N., Mustaev, A., Murakami, K., Nair, S., Goldfarb, A., Darst, S.A. (2001). "Structural mechanism for rifampicin inhibition of bacterial RNA polymerase". Cell 104 (6): 901–12. doi:10.1016/S0092-8674(01)00286-0. PMID 11290327.

[Feklistov-5] Feklistov, A., Mekler, V., Jiang, Q., Westblade, L.F., Irschik, H., Jansen, R., Mustaev, A., Darst, S.A., Ebright, R.H. (2008). "Rifamycins do not function by allosteric modulation of binding of Mg2+ to the RNA polymerase active center". Proc Natl Acad Sci USA 105 (39): 14820–5. doi:10.1073/pnas.0802822105. PMID 18787125.

[6] Lancini, G.; Cavalleri, B. (1997). In Biotechnology of Antibiotics. Marcel Dekker, New York, USA. p. 521.

[Floss2005-7] Floss, H.G.; Yu, T. (2005). "Rifamycin-Mode of Action, Resistance, and Biosynthesis". Chem. Rev. 105 (2): 621–32. doi:10.1021/cr030112j. PMID 15700959.

[8] Guo, J.; Frost, J.W. (2002). "Kanosamine Biosynthesis: A Likely Source of the Aminoshikimate Pathway's Nitrogen Atom". J. Am. Chem. Soc. 124 (36): 10642–3. doi:10.1021/ja026628m. PMID 12207504.

[9] 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 (36): 10644–5. doi:10.1021/ja0206339. PMID 12207505.

[10] Guo, J.; Frost, J.W. (2002). "Biosynthesis of 1-Deoxy-1-imino-d-erythrose 4-Phosphate: A Defining Metabolite in the Aminoshikimate Pathway". J. Am. Chem. Soc. 124 (4): 528–9. doi:10.1021/ja016963v. PMID 11804477.

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rifamycin