Macrolide antibiotics

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Chapter: Medicinal Chemistry : Antibiotics

The macrolide antibacterial agents are extremely useful chemotherapeutic agents for the treatment of a variety of infectious disorders and diseases caused by a host of gram-positive bacteria, both cocci and bacilli;


Macrolide antibiotics

The macrolide antibacterial agents are extremely useful chemotherapeutic agents for the treatment of a variety of infectious disorders and diseases caused by a host of gram-positive bacteria, both cocci and bacilli; they also exhibit useful effectiveness against gram-negative cocci, specially, neisseria spp. The macrolides are commonly administered for respiratory, skin, tissue, and genitourinary infections caused by these pathogens.

Chemistry: They are characterized by five common chemical features.

1.         A macrocyclic lactone usually has 12–17 atoms, hence the name macrolide.

2.         A ketone group.

3.         One or two amino sugars glycosidically linked to the nucleus.

4.         A neutral sugar linked either to amine sugar or to nucleus.

5.         The presence of dimethyl amino moiety on the sugar residue, which explains the basicity of these compounds, and consequently the formation of salts. The antibacterial spectrum of activity of the more potent macrolides resembles that of penicillin. Examples: erythromycin, oleandomycin, clarithromycin, flurithromycin, dirithomycin, azithromycin.

 

i. Azithromycin


Properties and uses: Azithromycin is a white powder, practically insoluble in water, soluble in anhydrous ethanol and methylene chloride. It is very stable under acidic conditions, is less active against Streptococci and Staphylococci than erythromycin, and is far more active against respiratory infections due to H. influenzae and Chlamydia trachomatis.


Acid degradation of erythromycin

Erythromycin is unstable in the acid media. The C-6 hydroxyl group reversibly attacks the C-9 ketone giving rise to a hemiketal intermediate. Dehydration prevents regeneration of the parent erythromycin and the C-12 hydroxyl group can subsequently add to produce a spiroketal species. The cladinose group is cleaved from the macrocycle and more harsh conditions lead to the release of desosamine. Useful antibacterial activity last till the dehydration of the hemiketal and the spiroketal is weakly active.


Mode of action: Macrolide antibiotics are bacteriostatic agents that inhibit protein synthesis by binding irreversibly to a site on the 50S subunits of the bacterial ribosome. Thus, inhibiting the translocation steps of protein synthesis at varying stages of peptide chain elongation (hinder the translocation of elongated peptide chain back from ‘A’ site to ‘P’ site). The macrolides inhibit ribosomal peptidyl transferase activity. Some macrolides also inhibit the translocation of the ribosome along with the mRNA template.

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