View source for Rifamycin

{{Short description|Group of antibiotics}}
{{Use dmy dates|date=March 2024}}
{{Infobox drug
| drug_name         = 
| image             = Rifamycin SV.svg
| image_class       = skin-invert-image
| width             = 
| alt               = 
| caption           = 
| image2            = Rifamycin SV stick 6BEB.png
| alt2              = 

<!-- Clinical data -->
| pronounce         = 
| tradename         = Aemcolo
| Drugs.com         = {{drugs.com|monograph|rifamycin-sodium}}
| MedlinePlus       = a619010
| DailyMedID        = Rifamycin
| pregnancy_AU      = <!-- A/B1/B2/B3/C/D/X -->
| pregnancy_AU_comment = 
| pregnancy_category= 
| routes_of_administration = [[By mouth]]
| class             = 

| ATC_prefix        = A07
| ATC_suffix        = AA13
| ATC_supplemental  = {{ATC|S01|AA16}} {{ATC|S02|AA12}} {{ATC|J04|AB03}} {{ATC|D06|AX15}}

<!-- Legal status -->
| legal_AU = <!-- S2, S3, S4, S5, S6, S7, S8, S9 or Unscheduled-->
| legal_AU_comment = 
| legal_BR =  <!-- OTC, A1, A2, A3, B1, B2, C1, C2, C3, C4, C5, D1, D2, E, F-->
| legal_BR_comment = 
| legal_CA = <!-- OTC, Rx-only, Schedule I, II, III, IV, V, VI, VII, VIII -->
| legal_CA_comment = 
| legal_DE = <!-- Anlage I, II, III or Unscheduled-->
| legal_DE_comment = 
| legal_NZ = <!-- Class A, B, C -->
| legal_NZ_comment = 
| legal_UK = <!-- GSL, P, POM, CD, CD Lic, CD POM, CD No Reg POM, CD (Benz) POM, CD (Anab) POM or CD Inv POM / Class A, B, C -->
| legal_UK_comment = 
| legal_US = Rx-only
| legal_US_comment = 
| legal_UN = <!-- N I, II, III, IV / P I, II, III, IV-->
| legal_UN_comment = 
| legal_status      = <!--For countries not listed above-->

<!-- Identifiers -->
| index2_label = as salt
| CAS_number        = 6998-60-3
| CAS_supplemental  = 
| PubChem           = 6324616
| PubChemSubstance  = 
| IUPHAR_ligand     = 
| DrugBank          = DB11753
| ChemSpiderID      = 16735998
| UNII              = DU69T8ZZPA
| KEGG              = D02549
| KEGG2             = D08480
| ChEBI             = 29673
| ChEMBL            = 437765
| NIAID_ChemDB      = 
| PDB_ligand        = 
| synonyms          = 

<!-- Chemical and physical data -->
| IUPAC_name        = 
| C=37 | H=47 | N=1 | O=12
| SMILES            = CC1C=CC=C(C(=O)NC2=CC(=C3C(=C2O)C(=C(C4=C3C(=O)C(O4)(OC=CC(C(C(C(C(C(C1O)C)O)C)OC(=O)C)C)OC)C)C)O)O)C
| StdInChI          = 1S/C37H47NO12/c1-16-11-10-12-17(2)36(46)38-23-15-24(40)26-27(32(23)44)31(43)21(6)34-28(26)35(45)37(8,50-34)48-14-13-25(47-9)18(3)33(49-22(7)39)20(5)30(42)19(4)29(16)41/h10-16,18-20,25,29-30,33,40-44H,1-9H3,(H,38,46)/b11-10+,14-13+,17-12-/t16-,18+,19+,20+,25-,29-,30+,33+,37-/m0/s1
| StdInChI_comment  = 
| StdInChIKey       = HJYYPODYNSCCOU-ODRIEIDWSA-N
| density           = 
| density_notes     = 
| melting_point     = 
| melting_high      = 
| melting_notes     = 
| boiling_point     = 
| boiling_notes     = 
| solubility        = 
| sol_units         = 
| specific_rotation = 
}}

The '''rifamycins''' are a group of [[antibiotic]]s that are synthesized either naturally by the bacterium ''[[Amycolatopsis rifamycinica]]'' or artificially. They are a subclass of the larger family of [[ansamycin]]s.  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]], [[rifalazil]] and [[rifaximin]]. Rifamycin, sold under the trade name Aemcolo, is approved in the United States for treatment of travelers' diarrhea in some circumstances.<ref>{{cite journal | vauthors = Lin SW, Lin CJ, Yang JC | title = Rifamycin SV MMX for the treatment of traveler's diarrhea | journal = Expert Opinion on Pharmacotherapy | volume = 18 | issue = 12 | pages = 1269–1277 | date = August 2017 | pmid = 28697313 | doi = 10.1080/14656566.2017.1353079 | s2cid = 8853242 }}</ref><ref>{{Cite press release|url=https://www.fda.gov/news-events/press-announcements/fda-approves-new-drug-treat-travelers-diarrhea|archive-url=https://web.archive.org/web/20191215203520/https://www.fda.gov/news-events/press-announcements/fda-approves-new-drug-treat-travelers-diarrhea|archive-date=15 December 2019|title=FDA approves new drug to treat travelers' diarrhea|website=U.S. [[Food and Drug Administration]] (FDA)|date=16 November 2018|access-date=19 November 2018}}</ref><ref>{{cite web | title=Drug Approval Package: Aemcolo (rifamycin) | website=U.S. [[Food and Drug Administration]] (FDA) | date=21 December 2018 | url=https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/210910Orig1_toc.cfm | access-date=27 December 2019}}</ref>

The name "rifamycin" (originally "rifomycin") was derived from the 1955 French film ''[[Rififi]]''.<ref name="pmid6635432">{{cite journal|doi=10.1093/clinids/5.Supplement_3.S402 |title=History of the Development of Rifampin |date=1983 |last1=Sensi |first1=P. |journal=Clinical Infectious Diseases |volume=5 |issue=Suppl 3 |pages=S402–S406 |pmid=6635432 }}</ref>{{rp|p=S402|q=At that time, we adopted both a code number (ME/83) and a nickname (Rififi) for the specific antibacterial substances selected for more extensive evaluation. The nickname Rififi was taken from the title of a French movie popular at that time and was the root of the common name rifamycins (originally rifomycins) that was given to these antimicrobial agents.}}

== Bacterium ==
[[Amycolatopsis rifamycinica|''Streptomyces mediterranei'']] was first isolated in 1957 from a soil sample collected near the beach-side town of [[Saint-Raphaël, Var|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.<ref name="MargalithBeretta1960">{{cite journal|vauthors = Margalith P, Beretta G|title=Rifomycin. XI. taxonomic study on streptomyces mediterranei nov. sp.|journal=Mycopathologia et Mycologia Applicata|volume=13|issue=4|year=1960|pages=321–330|issn=0301-486X|doi=10.1007/BF02089930|s2cid=23241543}}</ref>

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 ribosomal RNA]] 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. Initially, a family  of closely related antibiotics was discovered referred to as Rifamycin A, B, C, D, E. The only component of this mixture sufficiently stable to isolate in a pure form was Rifamycin&nbsp;B, which was poorly active. However, further studies showed that while Rifamycin&nbsp;B was essentially inactive, it was spontaneously oxidized and hydrolyzed in aqueous solutions to yield the highly active Rifamycin&nbsp;S. Simple reduction of Rifamycin&nbsp;S yielded the hydroquinone form called Rifamycin&nbsp;SV, which became the first member of this class to enter clinical use as an intravenous antibiotic. Further chemical modification of Rifamycin&nbsp;SV yielded an improved analog Rifamide, which was also introduced into clinical practice, but was similarly limited to intravenous use. After an extensive modification program, Rifampin was eventually produced, which is orally available and has become a mainstay of tuberculosis therapy<ref name="pmid6635432"/>
[[Image:Rifamycin B and SV.png|class=skin-invert-image|550 px|center]]

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. A systematic review of clinical trials on alternative regimens for prevention of active tuberculosis in HIV-negative individuals with latent TB found that a weekly, directly observed regimen of [[rifapentine]] with [[isoniazid]] for three months was as effective as a daily, self-administered regimen of isoniazid for nine months. But the rifapentine-isoniazid regimen had higher rates of treatment completion and lower rates of [[hepatotoxicity]]. However, the rate of treatment-limiting adverse events was higher in the rifapentine-isoniazid regimen.<ref>{{cite journal | vauthors = Sharma SK, Sharma A, Kadhiravan T, Tharyan P | title = Rifamycins (rifampicin, rifabutin and rifapentine) compared to isoniazid for preventing tuberculosis in HIV-negative people at risk of active TB | journal = The Cochrane Database of Systematic Reviews | volume = 2013 | issue = 7 | article-number = CD007545 | date = July 2013 | pmid = 23828580 | pmc = 6532682 | doi = 10.1002/14651858.CD007545.pub2 }}</ref>

The rifamycins have  a unique mechanism of action, [[Enzyme inhibitor|selectively inhibiting]] bacterial DNA-dependent [[RNA polymerase]], and show no cross-resistance with other antibiotics in clinical use. However, despite their activity against bacteria [[Multiple drug resistance|resistant to other antibiotics]], the rifamycins themselves suffer from a rather high frequency of resistance. Because of this, Rifampin  and other rifamycins are typically  used in  combination with other antibacterial drugs. This is routinely practiced in TB therapy and serves to prevent the formation of mutants that are resistant to any of the drugs in the combination. Rifampin 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.<ref>{{cite journal | vauthors = Pozniak AL, Miller R, Ormerod LP | title = The treatment of tuberculosis in HIV-infected persons | journal = AIDS | volume = 13 | issue = 4 | pages = 435–445 | date = March 1999 | pmid = 10197371 | doi = 10.1097/00002030-199907300-00035 | doi-access = free }}</ref>  In addition, rifabutin and rifapentine have both been used against tuberculosis acquired in HIV-positive patients. Although Tuberculosis therapy remains the most important use of Rifampin, an increasing  problem with serious Multiple Drug Resistant bacterial infections has led to some  use of antibiotic combinations containing Rifampin to treat them.

== Mechanism of action ==
The antibacterial activity of rifamycins relies on the inhibition of bacterial DNA-dependent RNA synthesis.<ref>{{cite journal | vauthors = Calvori C, Frontali L, Leoni L, Tecce G | title = Effect of rifamycin on protein synthesis | journal = Nature | volume = 207 | issue = 995 | pages = 417–418 | date = July 1965 | pmid = 4957347 | doi = 10.1038/207417a0 | s2cid = 4144738 | bibcode = 1965Natur.207..417C }}</ref>  This is due to the high affinity of rifamycins for the  prokaryotic [[RNA polymerase]]. The selectivity of the rifamycins depends on the fact that they have a very poor affinity for  the analogous mammalian enzyme.  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).<ref name="Campbell">{{cite journal | vauthors = Campbell EA, Korzheva N, Mustaev A, Murakami K, Nair S, Goldfarb A, Darst SA | title = Structural mechanism for rifampicin inhibition of bacterial rna polymerase | journal = Cell | volume = 104 | issue = 6 | pages = 901–912 | date = March 2001 | pmid = 11290327 | doi = 10.1016/S0092-8674(01)00286-0 | s2cid = 8229399 | doi-access = free }}</ref><ref name="Feklistov">{{cite journal | vauthors = Feklistov A, Mekler V, Jiang Q, Westblade LF, Irschik H, Jansen R, Mustaev A, Darst SA, Ebright RH | display-authors = 6 | title = Rifamycins do not function by allosteric modulation of binding of Mg2+ to the RNA polymerase active center | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 105 | issue = 39 | pages = 14820–14825 | date = September 2008 | pmid = 18787125 | pmc = 2567451 | doi = 10.1073/pnas.0802822105 | doi-access = free | bibcode = 2008PNAS..10514820F }}</ref>  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. Single step high level resistance to the rifamycins occurs as the result of a single amino acid change in the bacterial DNA dependent RNA polymerase.

== Biosynthesis ==
The first information on [[biosynthesis]] of the rifamycins came from studies using the stable isotope Carbon-13 and [[Nuclear magnetic resonance|NMR spectroscopy]] to establish the origin of the carbon skeleton. These studies showed that the ansa chain was derived from [[acetate]] and [[propionate]], in common with other [[polyketide]] antibiotics. The [[Naphthalene|naphthalenic]] chromophore was shown to derive from a propionate unit coupled with a seven carbon amino moiety of unknown origin. The general scheme of biosynthesis starts with the uncommon starting unit, 3-amino-5-hydroxybenzoic acid ('''AHBA'''), via type I polyketide pathway ('''PKS I''') in which chain extension is performed using 2 acetate and 8 propionate units.<ref>{{cite book | vauthors = Lancini G, Cavalleri B | chapter = Vancomycin and other glycopeptides | veditors = Strohl GR |title= Biotechnology of Antibiotics |year=1997 |page=521|publisher= Marcel Dekker | location = New York, USA}}</ref> 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''.<ref name="Floss2005">{{cite journal | vauthors = Floss HG, Yu TW | title = Rifamycin-mode of action, resistance, and biosynthesis | journal = Chemical Reviews | volume = 105 | issue = 2 | pages = 621–632 | date = February 2005 | pmid = 15700959 | doi = 10.1021/cr030112j }}</ref>

[[Image:AHBA_biosyn1.png|class=skin-invert-image|center]]
[[Image:Rifamycin biosynthesis.gif|class=skin-invert-image|center]]
[[Image:Rifamycin biosynthesis2.gif|class=skin-invert-image|center]]

The ''rif'' cluster is responsible for the biosynthesis of rifamycins. It contains genes ''{{Not a typo|rifG}}'' through ''{{Not a typo|rifN}}'', which were shown to biosynthesize AHBA. ''{{Not a typo|RifK}}'', ''{{Not a typo|rifL}}'', ''{{Not a typo|rifM}}'', and ''{{Not a typo|rifN}}'' are believed to act as [[transaminase]]s in order to form the AHBA precursor kanosamine.<ref>{{cite journal | vauthors = Guo J, Frost JW | title = Kanosamine biosynthesis: a likely source of the aminoshikimate pathway's nitrogen atom | journal = Journal of the American Chemical Society | volume = 124 | issue = 36 | pages = 10642–10643 | date = September 2002 | pmid = 12207504 | doi = 10.1021/ja026628m | bibcode = 2002JAChS.12410642G }}</ref><ref>{{cite journal | vauthors = Arakawa K, Müller R, Mahmud T, Yu TW, Floss HG | title = 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 | journal = Journal of the American Chemical Society | volume = 124 | issue = 36 | pages = 10644–10645 | date = September 2002 | pmid = 12207505 | doi = 10.1021/ja0206339 | bibcode = 2002JAChS.12410644A }}</ref> "RifH" encodes aminoDAHP synthase that catalyzes the condensation between 1-deoxy-1-imino-d-erythrose 4-phosphate and [[phosphoenolpyruvate]].<ref>{{cite journal | vauthors = Guo J, Frost JW | title = Biosynthesis of 1-deoxy-1-imino-D-erythrose 4-phosphate: a defining metabolite in the aminoshikimate pathway | journal = Journal of the American Chemical Society | volume = 124 | issue = 4 | pages = 528–529 | date = January 2002 | pmid = 11804477 | doi = 10.1021/ja016963v | bibcode = 2002JAChS.124..528G }}</ref> ''{{Not a typo|RifA}}'' through ''{{Not a typo|rifE}}'' encode a type I polyketide synthase module, with the loading module being a [[Nonribosomal peptide|non-ribosomal peptide synthetase]]. In all, ''{{Not a typo|rifA-E}}'' assemble a linear undecaketide and are followed by ''{{Not a typo|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.

[[Image:Biosyn_genes1.png|class=skin-invert-image|center]]

== Derivatives ==
Lepetit introduced Rifampicin, an orally active rifamycin, in 1966.<ref name="reddy">{{cite journal | vauthors = Reddy DS, Sinha A, Kumar A, Saini VK | title = Drug re-engineering and repurposing: A significant and rapid approach to tuberculosis drug discovery | journal = Archiv der Pharmazie | volume = 355 | issue = 11 | pages = e2200214 | date = November 2022 | article-number = 2200214 | pmid = 35841594 | doi = 10.1002/ardp.202200214 | s2cid = 250582950 }}</ref> [[Rifabutin]], a derivative of rifamycin S, was invented by Italian drug manufacturer [[Achifar]] in 1975 and came onto the US market in 1992.<ref name=reddy/> Hoechst Marion Roussel (now part of [[Aventis]]) introduced [[rifapentine]] to the US market in 1998, with Achifar having synthesized it in 1965.<ref>{{cite journal | vauthors = Guglielmetti L, Günther G, Leu C, Cirillo D, Duarte R, Garcia-Basteiro AL, Goletti D, Jankovic M, Kuksa L, Maurer FP, Méchaï F, Tiberi S, van Leth F, Veziris N, Lange C | display-authors = 6 | title = Rifapentine access in Europe: growing concerns over key tuberculosis treatment component | journal = The European Respiratory Journal | volume = 59 | issue = 5 | date = May 2022 | pmid = 35589114 | pmc = 9186306 | doi = 10.1183/13993003.00388-2022 | doi-access = free }}</ref> Use of rifapentine remains uncommon as a treatment for [[pulmonary tuberculosis]], and treatment with rifapentine is given on the basis of careful selection of patients.<ref>{{cite journal | vauthors = Munsiff SS, Kambili C, Ahuja SD | title = Rifapentine for the treatment of pulmonary tuberculosis | journal = Clinical Infectious Diseases | volume = 43 | issue = 11 | pages = 1468–1475 | date = December 2006 | pmid = 17083024 | doi = 10.1086/508278 | doi-access = free }}</ref>

[[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]].<ref>{{cite journal | vauthors = Ojetti V, Lauritano EC, Barbaro F, Migneco A, Ainora ME, Fontana L, Gabrielli M, Gasbarrini A | display-authors = 6 | title = Rifaximin pharmacology and clinical implications | journal = Expert Opinion on Drug Metabolism & Toxicology | volume = 5 | issue = 6 | pages = 675–682 | date = June 2009 | pmid = 19442033 | doi = 10.1517/17425250902973695 | s2cid = 41970585 }}</ref>

== Available rifamycins ==
{{unreferenced section|date=December 2019}}
* [[Rifampicin]] or Rifampin
* [[Rifabutin]]
* [[Rifapentine]]
* [[Rifaximin]]
* Aemcolo<ref>{{cite web | title = AEMCOLO (rifamycin) delayed-release tablets, for oral use. | url = https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210910s000lbl.pdf | archive-url = https://web.archive.org/web/20200124193858/https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210910s000lbl.pdf | archive-date = 24 January 2020 | work = Aries Pharmaceuticals, Inc. | publisher = U.S. Food and Drug Administration | date = 2018 }}</ref><ref>{{cite web | url=https://www.webmd.com/drugs/2/drug-176598/aemcolo-oral/details | title= Aemcolo Oral: Uses, Side Effects, Interactions, Pictures, Warnings & Dosing | work = WebMD }}</ref>

== References ==
{{reflist}}

== Further reading ==
{{refbegin}}
* {{cite journal | vauthors = Sensi P, Margalith P, Timbal MT | title = Rifomycin, a new antibiotic; preliminary report | journal = Il Farmaco; Edizione Scientifica | volume = 14 | issue = 2 | pages = 146–147 | date = 1959 | pmid = 13639988 | doi = | url = }} - the paper announcing the discovery of the rifamycins.
* {{cite journal | vauthors = Thiemann JE, Zucco G, Pelizza G | title = A proposal for the transfer of Streptomyces mediterranei Margalith and Beretta 1960 to the genus Nocardia as Nocardia mediterranea (Margalith and Beretta) comb. nov | journal = Archiv für Mikrobiologie | volume = 67 | issue = 2 | pages = 147–155 | date = 1969 | pmid = 5386179 | doi = 10.1007/BF00409680 | bibcode = 1969ArMic..67..147T | s2cid = 19596120 }} - the paper which renamed ''Streptomyces mediterranei'' as ''Nocardia mediterranei''.
* {{cite journal | vauthors = Lechevalier MP, Prauser H, Labeda DP, Ruan JS | title = Two new genera of nocardioform actinomycetes: Amycolata gen. nov. and Amycolatopsis gen. nov. | journal = International Journal of Systematic and Evolutionary Microbiology | date = January 1986 | volume = 36 | issue = 1 | pages = 29–37 | doi = 10.1099/00207713-36-1-29 | doi-access = free }} - the paper which renamed ''Nocardia mediterranei'' as ''Amycolatopsis mediterranei''.
* {{cite journal | vauthors = Bala S, Khanna R, Dadhwal M, Prabagaran SR, Shivaji S, Cullum J, Lal R | title = Reclassification of Amycolatopsis mediterranei DSM 46095 as Amycolatopsis rifamycinica sp. nov | journal = International Journal of Systematic and Evolutionary Microbiology | volume = 54 | issue = Pt 4 | pages = 1145–1149 | date = July 2004 | pmid = 15280283 | doi = 10.1099/ijs.0.02901-0 | doi-access = free }} - the paper with the latest name change
{{refend}}

{{Antimycobacterials}}
{{Otologicals}}
{{Nucleic acid inhibitors}}
{{portal bar | Medicine}}

[[Category:CYP3A4 inducers]]
[[Category:Rifamycin antibiotics]]
[[Category:Otologicals]]