Macrolide Antibiotics Introduction The term macrolide is derived from its characteristic large (14-membered) lactone (cyclic ester) ring. The clinically essential members of this antibiotic family have two / more characteristics of sugar attached to this ring. One of these sugars usually carries a substituted amino group, so their overall chemical character is weakly basic. More than 3 dozen such compounds are known but only a few are medicinally used (two erythromycins and oleandomycin are medically used).
Mode of action
Macrolide antibiotics are bacteriostatic agents that inhibit protein synthesis by irreversibly binding to a site on the 50S subunits of the bacterial ribosome. Thus, inhibiting the translocation steps of protein synthesis at various stages of peptide chain elongation (preventing the transfer of long peptide chain from the “A” site to the “P” site). Macrolides inhibit the activity of ribosomal peptidyl transferase. Some macrolides also prevent ribosome translocation along with the mRNA template.
The macrolide antibacterial agents are beneficial chemotherapeutic agents for the treatment of a variety of infectious disorders and diseases caused by a host of gram-positive bacterial pathogens. These agents are exemplified by erythromycin and are generally effective against streptococcus, staphylococcus, chlamydia, legionella, and mycoplasma. As a result, the macrolides are commonly administered for respiratory, skin, tissue, and genitourinary infection caused by these pathogens.
Clarithromycin is the 6-methyl ether of erythromycin. The simple methylation of the C-6 hydroxyl group of erythromycins creates a semi-synthetic derivative that fully retains the antibacterial properties of the parent antibiotic. With markedly increased acid stability and oral bioavailability and reduced GI-side effects associated with erythromycin. Clarithromycin is well absorbed following oral administration (bioavailability 50—55%). Extensive oxidation and hydrolysis occur in the liver. The major metabolite is the 14-hydroxyl derivative, which retains antibacterial activity. Some of the microbiological properties of clarithromycin also appear to be superior to those of erythromycin. It exhibits greater potency against M. pneumoniae, legionella species, chlamydia pneumoniae, H. influenza, and M. catarrhalis than erythromycin.
It is also significantly more active than erythromycin against A. streptococci, S. pneumonia, etc. in vivo because of its superior oral bioavailability. However, it is more expensive.
Adverse reactions to clarithromycin are rare.
The azides (e. g azithromycin) are semi-synthetic 15-membered congeners in which N-atom has been introduced to expand a 14-membered precursor. This leads to an extended spectrum of action e. g Azithromycin which is a semi-synthetic derivative of erythromycin, prepared by Beckman rearrangement of the corresponding 6-oxime, followed by N-methylation and reduction of the resulting ring-expended lactam. Removal of the 9-keto group coupled with the incorporation of a weakly basic tertiary amine nitrogen into the macrolide ring increases the stability of azithromycin to acid-catalyzed degradation. These changes also increase the lipid-solubility of the molecule, thereby conferring unique pharmacokinetic and microbiological properties. Its oral bioavailability of it is good.
The spectrum of antibacterial activity of azithromycin is similar to that observed for erythromycin and clarithromycin but with some interesting differences generally, it is more active against gram-negative bacteria and less active against gram-positive bacteria than its close relatives.