Antibiotics.. Tetracyclines. Aminoglycoside. Macrolides. Chloramphenicol

Transcription

1 Antibiotics. Tetracyclines. Aminoglycoside. Macrolides. Chloramphenicol

2 Antibiotics as disturber with the biosynthesis of protein These antibiotics all target the bacterial ribosome and interfere in the process of translation of the messenger RNA into protein and thus block a fundamental process in bacterial metabolism. Inhibitors of 30s Ribosomal subunit: Aminoglycosides and Tetracyclines Inhibitors of the 50s Ribosomal subunit: Macrolides and Chloramphenicol

3 Macrolide Antibiotics

4 Macrolide Antibiotics Naturally occurring macrolide antibiotics are grouped into three major groups of 12-, 14-, and 16-membered macrolides with the aglycone consisting of 12-, 14-, and 16-atom cyclic lactone rings, respectively. For example, erythromycin A is a 14-membered macrolide (a 14- atom cyclic lactone ring) and possesses desosamine and cladinose glycosidically linked to C-5 and C-3, respectively.

5 Mechanism of action The mechanism of action of macrolides is that: it inhibits bacteria by interfering with programmed ribosomal protein biosynthesis by inhibiting translocation of amino acid m-rna following binding to the 50s subunit.

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7 Erythromycin Erythromycin is an orally effective antibiotic discovered in 1952 in the metabolic products of a strain of Streptomyces eryyhreus, it includes Erythromycin A, B, and C. The component A is used in clinic primarily. It is active for most G-P and some G-N.

8 Erythromycin Erythronolide A H H H H N 3' 1' 1" 3" H Me Desosamine Cladinose Erythromycin A A and B A C-12=-H B C-12=-H A and C A C-3"= C C-3"=-H

9 Extremely unstable under acid condition (rapid internal cyclic ketal formation). H H H H sugar H+ H H sugar sugar sugar H+ -H 2 H+ H+ H sugar H sugar H sugar sugar

10 Simply modification of erythromycin -Ester Pro-drug H 9 6 R 2'' N Basic group H H C 2 H 5 1 H Name of compound R Salt Erythromycin Base H Erythromycin Hydrochloride H HCl Erythromycin Estolate CCH 2 (CH 2 ) 11 S 3 H Erythromycin Ethylsuccinate C(CH 2 ) 2 C 2 C 2 H 5 Erythromycin Stearate H (CH 2 ) 16 C 2 H

11 ther main structure features of macrolides are: Two or more sugars glycosidically linked to the 14 atoms large lactone ring. The 3-L-cladinose sugar is suggested to be the cause of the GI disturbance resulting from the release of motilin (Peptide (22 residues) found in duodenum and pituitary that stimulates intestinal motility. Erythromycin Estolate It is a C-2''-propionic acid ester, N-lauryl sulfate salt. In a small number of cases it produces a severe, dose-related cholestatic jaundice in which the bile becomes granular in the bile duct, impeding flow so that the bile salts back up into circulation.

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13 Strategy for erythromycin modification

14 N H H 6 H C 2 H 5 Clarithromycin H C-14 hydroxy analogue Clarithromycin with 6- group, avoiding internal hemiketalization It is subjected to first-pass liver metabolism that leads to formation of its C-14 hydroxy analogue which even has greater antimicrobial potency, especially against Haemophilus influenzae.

15 Erythromycin derivatives F H H H H H N H H N H H ú ºì ùËØ Flunithromycin ËÀ ùËØ Clarithromycin

16 Azithromycin (azalide) N H 9 N 9a H CH C H 10 H H C 2 H 5 Azithromycin H Azithromycin has longer half-life, attributed to longer tissue penetration, allowing once-a-day dosage. It should be taken on an empty stomach, yet, it produces metallic taste.

17 Dirithromycin H N C 2 H 5 H H H N H H 2 N H C 2 H 5 H H H N H Dirithromycin Prodrug Erythromycyclamine Active form Prepared by condensation of erythromycyclamine with 2-(2- methoxyethoxy)acetaldehyde. It is more acid stable compared to erythromycin and on passage through the gut it is converted to erythromycyclamine (active drug).

18 Ketolides They are characterized by reduction of the 3-H to ketone. They are active against erythromycin resistant microorganisms.

19 Telithromycin Telithromycin is the first ketolide(3-keto macrolide derivatives). It is prepared by removing the cladinose sugar from the C-3 position of the erythronolide skeleton reduces gastric upset resulting from the release of motilin. and oxidizing the remaining hydroxyl group to a keto group.

20 In addition to the C-3 ketone, telithromycin has an aromatic N- substituted carbamate extension at position C-11 and C-12. This ring has an imidazo-pyridyl group attachment greatly improves binding at active sites. Telithromycin possesses a 6- group (like clarithromycin), avoiding internal hemiketalization with the 3- keto function and giving the ketolide molecule excellent acid stability. The ketolides are very active against respiratory pathogens, including erythromycin-resistant strains

21 Development of bacterial resistance First Bacteria possessing R-factor enzymes can methylate a specific guanine residue on their own ribosomal. Second The mutation of adenine to guanine which results in 10,000 fold reduction of binding capacity of erythromycin and clarithromycin. Third Some bacterial strains appear to be resistant to macrolides due to an active efflux process in which the drug expelled from the cell.

22 Summary Tetracyclines H H Macrolides Erythromycin Structure modification of semi-synthetic erythromycin H H H N Mechanism of action

23 Question: 1. Why is the erythromycin A unstable in acidic condition? 2. What is the difference of the action mechanism of antibiotics? Assignment:

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