Rifamycin

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Rifamycin
Rifamycin SV.svg
Rifamycin SV stick 6BEB.png
Clinical data
Trade names Aemcolo
AHFS/Drugs.com Monograph
MedlinePlus a619010
License data
Routes of
administration
By mouth
ATC code
Legal status
Legal status
Identifiers
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
Chemical and physical data
Formula C37H47NO12
Molar mass 697.778 g·mol−1
3D model (JSmol)
  • 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
  • InChI=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
  • Key:HJYYPODYNSCCOU-ODRIEIDWSA-N

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

Contents

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. [1] [2] [3]

The name "rifamycin" (originally "rifomycin") was derived from the 1955 French film Rififi . [4] :S402

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. [5]

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 B, which unfortunately was poorly active. However, further studies showed that while Rifamycin B was essentially inactive, it was spontaneously oxidized and hydrolyzed in aqueous solutions to yield the highly active Rifamycin S. Simple reduction of Rifamycin S yielded the hydroquinone form called Rifamycin SV, which became the first member of this class to enter clinical use as an intravenous antibiotic. Further chemical modification of Rifamycin 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 [4]

Rifamycin B and SV.png

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. [6]

The rifamycins have a unique mechanism of action, selectively inhibiting bacterial DNA-dependent RNA polymerase, and show no cross-resistance with other antibiotics in clinical use. However, despite their activity against bacteria 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. [7] 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. [8] 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). [9] [10] 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 the biosynthesis of the rifamycins came from studies using the stable isotope Carbon-13 and 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 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. [11] 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. [12]

AHBA biosyn1.png
Rifamycin biosynthesis.gif
Rifamycin biosynthesis2.gif

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. [13] [14] "RifH" encodes aminoDAHP synthase that catalyzes the condensation between 1-deoxy-1-imino-d-erythrose 4-phosphate and phosphoenolpyruvate. [15] RifA through rifE encode a type I polyketide synthase module, with the loading module being a non-ribosomal peptide synthetase. 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.

Biosyn genes1.png

Derivatives

Lepetit introduced Rifampicin, an orally active rifamycin, in 1966. [16] Rifabutin, a derivative of rifamycin S, was invented by Italian drug manufacturer Achifar in 1975 and came onto the US market in 1992. [16] Hoechst Marion Roussel (now part of Aventis) introduced rifapentine to the US market in 1998, with Achifar having synthesized it in 1965. [17] 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. [18]

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. [19]

Available rifamycins

Related Research Articles

<i>Mycobacterium tuberculosis</i> Species of pathogenic bacteria that causes tuberculosis

Mycobacterium tuberculosis, also known as Koch's bacillus, is a species of pathogenic bacteria in the family Mycobacteriaceae and the causative agent of tuberculosis. First discovered in 1882 by Robert Koch, M. tuberculosis has an unusual, waxy coating on its cell surface primarily due to the presence of mycolic acid. This coating makes the cells impervious to Gram staining, and as a result, M. tuberculosis can appear weakly Gram-positive. Acid-fast stains such as Ziehl–Neelsen, or fluorescent stains such as auramine are used instead to identify M. tuberculosis with a microscope. The physiology of M. tuberculosis is highly aerobic and requires high levels of oxygen. Primarily a pathogen of the mammalian respiratory system, it infects the lungs. The most frequently used diagnostic methods for tuberculosis are the tuberculin skin test, acid-fast stain, culture, and polymerase chain reaction.

<span class="mw-page-title-main">Isoniazid</span> Antibiotic for treatment of tuberculosis

Isoniazid, also known as isonicotinic acid hydrazide (INH), is an antibiotic used for the treatment of tuberculosis. For active tuberculosis, it is often used together with rifampicin, pyrazinamide, and either streptomycin or ethambutol. For latent tuberculosis, it is often used alone. It may also be used for atypical types of mycobacteria, such as M. avium, M. kansasii, and M. xenopi. It is usually taken by mouth, but may be used by injection into muscle.

<span class="mw-page-title-main">Rifampicin</span> Antibiotic medication

Rifampicin, also known as rifampin, is an ansamycin antibiotic used to treat several types of bacterial infections, including tuberculosis (TB), Mycobacterium avium complex, leprosy, and Legionnaires' disease. It is almost always used together with other antibiotics with two notable exceptions: when given as a "preferred treatment that is strongly recommended" for latent TB infection; and when used as post-exposure prophylaxis to prevent Haemophilus influenzae type b and meningococcal disease in people who have been exposed to those bacteria. Before treating a person for a long period of time, measurements of liver enzymes and blood counts are recommended. Rifampicin may be given either by mouth or intravenously.

<span class="mw-page-title-main">Management of tuberculosis</span> Disease treatment

Management of tuberculosis refers to techniques and procedures utilized for treating tuberculosis (TB), or simply a treatment plan for TB.

<span class="mw-page-title-main">Mitomycins</span> Group of antibiotics

The mitomycins are a family of aziridine-containing natural products isolated from Streptomyces caespitosus or Streptomyces lavendulae. They include mitomycin A, mitomycin B, and mitomycin C. When the name mitomycin occurs alone, it usually refers to mitomycin C, its international nonproprietary name. Mitomycin C is used as a medicine for treating various disorders associated with the growth and spread of cells.

<i>Mycobacterium avium-intracellulare</i> infection Medical condition

Mycobacterium avium-intracellulare infection (MAI) is an atypical mycobacterial infection, i.e. one with nontuberculous mycobacteria or NTM, caused by Mycobacterium avium complex (MAC), which is made of two Mycobacterium species, M. avium and M. intracellulare. This infection causes respiratory illness in birds, pigs, and humans, especially in immunocompromised people. In the later stages of AIDS, it can be very severe. It usually first presents as a persistent cough. It is typically treated with a series of three antibiotics for a period of at least six months.

<span class="mw-page-title-main">Rifaximin</span> Antibiotic medication

Rifaximin, is a non-absorbable, broad spectrum antibiotic mainly used to treat travelers' diarrhea. It is based on the rifamycin antibiotics family. Since its approval in Italy in 1987, it has been licensed in over more than 30 countries for the treatment of a variety of gastrointestinal diseases like irritable bowel syndrome, and hepatic encephalopathy. It acts by inhibiting RNA synthesis in susceptible bacteria by binding to the RNA polymerase enzyme. This binding blocks translocation, which stops transcription. It is marketed under the brand name Xifaxan by Salix Pharmaceuticals.

<span class="mw-page-title-main">Geldanamycin</span> Chemical compound

Geldanamycin is a 1,4-benzoquinone ansamycin antitumor antibiotic that inhibits the function of Hsp90 by binding to the unusual ADP/ATP-binding pocket of the protein. HSP90 client proteins play important roles in the regulation of the cell cycle, cell growth, cell survival, apoptosis, angiogenesis and oncogenesis.

<span class="mw-page-title-main">Rifabutin</span> Chemical compound

Rifabutin (Rfb) is an antibiotic used to treat tuberculosis and prevent and treat Mycobacterium avium complex. It is typically only used in those who cannot tolerate rifampin such as people with HIV/AIDS on antiretrovirals. For active tuberculosis it is used with other antimycobacterial medications. For latent tuberculosis it may be used by itself when the exposure was with drug-resistant TB.

<span class="mw-page-title-main">Rifapentine</span> Chemical compound

Rifapentine, sold under the brand name Priftin, is an antibiotic used in the treatment of tuberculosis. In active tuberculosis it is used together with other antituberculosis medications. In latent tuberculosis it is typically used with isoniazid. It is taken by mouth.

The rpoB gene encodes the β subunit of bacterial RNA polymerase and the homologous plastid-encoded RNA polymerase (PEP). It codes for 1342 amino acids in E. coli, making it the second-largest polypeptide in the bacterial cell. It is targeted by the rifamycin family of antibacterials, such as rifampin. Mutations in rpoB that confer resistance to rifamycins do so by altering the protein's drug-binding residues, thereby reducing affinity for these antibiotics.

<span class="mw-page-title-main">Multidrug-resistant tuberculosis</span> Medical condition

Multidrug-resistant tuberculosis (MDR-TB) is a form of tuberculosis (TB) infection caused by bacteria that are resistant to treatment with at least two of the most powerful first-line anti-TB medications (drugs): isoniazid and rifampicin. Some forms of TB are also resistant to second-line medications, and are called extensively drug-resistant TB (XDR-TB).

<span class="mw-page-title-main">Ansamycin</span> Group of chemical compounds

Ansamycins is a family of bacterial secondary metabolites that show antimicrobial activity against many Gram-positive and some Gram-negative bacteria, and includes various compounds, including streptovaricins and rifamycins. In addition, these compounds demonstrate antiviral activity towards bacteriophages and poxviruses.

A nucleic acid inhibitor is a type of antibacterial that acts by inhibiting the production of nucleic acids. There are two major classes: DNA inhibitors and RNA inhibitors. The antifungal flucytosine acts in a similar manner.

The Xpert MTB/RIF is a cartridge-based nucleic acid amplification test (NAAT) for rapid tuberculosis diagnosis and rapid antibiotic sensitivity test. It is an automated diagnostic test that can identify Mycobacterium tuberculosis (MTB) DNA and resistance to rifampicin (RIF). It was co-developed by the laboratory of Professor David Alland at the University of Medicine and Dentistry of New Jersey (UMDNJ), Cepheid Inc. and Foundation for Innovative New Diagnostics, with additional financial support from the US National Institutes of Health (NIH).

The Aminoshikimate pathway is a biochemical pathway present in some plants, which has been studied by biologists, biochemists and especially those interested in manufacture of novel antibiotic drugs. The pathway is a novel variation of the shikimate pathway. The aminoshikimate pathway was first discovered and studied in the rifamycin B producer Amycolatopsis mediterranei. Its end product, 3-amino-5-hydroxybenzoate, serves as an initiator for polyketide synthases in the biosynthesis of ansamycins.

<i>Amycolatopsis orientalis</i> Species of bacterium

Amycolatopsis orientalis is a Gram-positive bacterium in the phylum Actinomycetota. It produces several substances with antimicrobial properties, including the antibiotic drug vancomycin.

<span class="mw-page-title-main">Naphthomycin A</span> Chemical compound

Naphthomycin A is a type of naphthomycin. It was isolated as a yellow pigment from Streptomyces collinus and it shows antibacterial, antifungal, and antitumor activities. Naphthomycins have the longest ansa aliphatic carbon chain of the ansamycin family. Biosynthetic origins of the carbon skeleton from PKS1 were investigated by feeding 13C-labeled precursors and subsequent 13C-NMR product analysis. Naphthomycin gene clusters have been cloned and sequenced to confirm involvement in biosynthesis via deletion of a 7.2kb region. Thirty-two genes were identified in the 106kb cluster.

Amycolatopsis rifamycinica is a species of Gram-positive bacteria in the genus Amycolatopsis. It produces the rifamycin antibiotics, which are used to treat mycobacterial diseases such as tuberculosis and leprosy. The type strain of Amycolatopsis rifamycinica has been reclassified several times. When it was first isolated from a French soil sample in 1957, it was identified as Streptomyces mediterranei. In 1969, the species was renamed Nocardia mediterranei because its cell wall was thought to resemble that of Nocardia species. The species was renamed Amycolatopsis mediterranei in 1986 after finding that it is not susceptible to Nocardia phage and has a cell wall that lacks mycolic acid. Finally, in 2004, it was determined that strain DSM 46095 represented a new species, independent of Amycolatopsis mediterranei, based on 16S ribosomal RNA sequencing. The new species was named Amycolatopsis rifamycinica.

Gladiolin is a polyketide natural product produced by Burkholderia gladioli BCC0238 which is isolated from sputum of cystic fibrosis patients. It was found to be a novel macrolide antibiotic which presented an activity against Mycobacterium tuberculosis. Gladiolin is structurally much more stable than its analogue etnangien as an efficient myxobacterial RNA polymerase inhibitor due to the lack of highly labile hexaene moiety in gladiolin. The good activity and high stability of gladiolin offers it the potential for further development as an antibiotic against antibiotic-resistant M. tuberculosis.

References

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Further reading