RIFAMYCIN
Introduction:
- It is a Class of Ansamycin antibiotics (Handle of basket)
- 'Ansa' means 'basket'
- Aliphatic Jain contain 17 atoms with C-O link at one end and CONH link at other end.
- The Cyclic structure is Naphthofuran ring.
- Firstly isolated in 1957 from soil sample in France containing a microorganisms.
- It is having first been classified as Streptomyces mediterranei, then Nocardia mediterranei and finally, Amycolatopsis mediterranei.
- Initially it contain only Rifamycin B (least biologically active, isolated in crystalline form).
- Rifamycin B converted to Rifamycin SV (increased Antibacterial Activity)
- Aliphatic Jain contain 17 atoms with C-O link at one end and CONH link at other end.
- The Cyclic structure is Naphthofuran ring.
- Firstly isolated in 1957 from soil sample in France containing a microorganisms.
- It is having first been classified as Streptomyces mediterranei, then Nocardia mediterranei and finally, Amycolatopsis mediterranei.
- Initially it contain only Rifamycin B (least biologically active, isolated in crystalline form).
- Rifamycin B converted to Rifamycin SV (increased Antibacterial Activity)
Therapeutic Indications for Rifamycin Antibacterials:
Synthesis:
- It occurs mainly by fermentation.
- You can see structure below. In this;
- You can see structure below. In this;
No. 3 and No. 4 --- it's substitution improved biological activity.
No. 1 and No. 8 --- oxygenated (OH,O) substitution, useful for chemical transformation.
No. 21 and No. 23 --- substitution with free hydroxyl group also improved activity.
- The key intermediate in the preparation of rifampicin and rifapentine is 3-formylrifamycin SV.
- 3-formylrifamycin SV is obtained by fermentation of A. mediterranei to give Rifamycin B which is then converted to Rifamycin SV.
No. 1 and No. 8 --- oxygenated (OH,O) substitution, useful for chemical transformation.
No. 21 and No. 23 --- substitution with free hydroxyl group also improved activity.
- The key intermediate in the preparation of rifampicin and rifapentine is 3-formylrifamycin SV.
- 3-formylrifamycin SV is obtained by fermentation of A. mediterranei to give Rifamycin B which is then converted to Rifamycin SV.
Bioavailability:
Rifampicin:
- Fastest and most completely absorb with oral bioavailability of 68%.
- Presence of food has effect upon its rate of absorption.
Rifabutin:
- Low bioavailability (20%).
- Presence of food also effect its rate of absorption.
Rifapentine:
- The absorption of rifa pentane is increased by food resulting in increased Cmax.
Rifaximin:
- It remain in GI tract to treat GI infections.
- It remains due to its permanently ionized nature.
Half-lives:
Rifampicin = 2-5 hrs
Rifapentine = 14-18 hrs
Rifabutin = 32-67 hrs
Metabolism:
- Largely excreted through bile into GI tract and faecally excreted.
- Relatively small proportion 10 to 25% excreted in urine, turning it a red-orange colour.
Mode of Action:
- Rifamycins are the first line requirement for TB, gram +ve (Staphylococcus aureus), gram - ve (Haemophilus influenzae), mycobacteria.
- Rifamycins are bactericidal, inhibition of RNAP.
- Bacterial RNAP consist of 5 sub-units (2 alpha, 2 beta and 1 gamma).
- Eukaryotic RNAP contains same 5 sub-units but also have 7-9 other sub-units.
Sigma Factor:
- Required in bacteria for the transcription of a particular gene.
- Rifamycin binds to Beta subunit.
REMEMBER!
- Rifamycin will be No longer sensitive in case of Oligonucleotide chain.
Q: why antibacterial agents that target RNAP are selective to bacteria and not eukaryote?
Ans: Because of differ in amino acid sequence.
Bacterial Resistance:
- Modification to a gene that encodes for Beta subunit.
Example:
1) M. tuberculosis
2) Non-mycobacterial organisms like Nocardia species
Indications:
Rifamycin:
- Gram -ve (Haemophilus influenzae, Neisseria meningitis), Gram +ve (M. tuberculosis).
Rifampicin:
- TB, Leprosy, Meningitis.
Adverse Effects:
- Hepatic Disease
- Immuno-allergic reactions
- Hepatotoxicity.
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