Erythromycin macrolides macrolide binding

Macrolides bind to the SOS ribosomal subunit of bacteria but not to the SOS mammalian ribosome this accounts for its selective toxicity. Binding to the ribosome occurs at a site near peptidyltransferase, with a resultant inhibition of translocation, peptide bond formation, and release of oligopeptidyl tRNA. However, unlike chloramphenicol, the macrolides do not inhibit protein synthesis by intact mitochondria, and this suggests that the mitochondrial membrane is not permeable to erythromycin. 

Macrolides bind to the SOS ribosomal subunit, in a manner similar to chloramphenicol and flor-fenicol, and interfere with bacterial protein synthesis. They are usually considered bacteriostatic but may be bactericidal at high concentrations. The antimicrobial activity of erythromycin is pH dependent. Optimum activity occurs at a pH of 8.8 activity is reduced in acidic environments such as abscesses. 

Macrolides bind to the 50s subunit of ribosomes. They are effective against a wide range of bacteria and are active orally. Erythromycin in particular is an alternative in individuals with penicillin hypersensitivity. 

Assuming that the major accumulation of erythromycin in S. aureus cells is determined by uptake dependent on the amounts of ribosome present in the cells, these observations of drug accumulation can be easily accounted for. As described in a previous section, erythromycin molecules can bind to ribosome at a certain equilibrium state expressed as a dissociation constant [39]. For example, on the supposition that an intracellular concentration of erythromycin increases by 30 times the level of that in an extracellular medium (1 pg/ml), the nonprotonated molecules of erythromycin (p T = 8.8) are able to occupy no more than 1% of a drug concentration present in S. aureus cell. That is why it is expected that intracellular pH would be 6.8 or less [200] and that erythromycin (even as a free base) with p T = 8.8 is one of the most water-soluble (i.e., deposition-resisting) drugs in the macrolide antibiotics (Table I). 

The macrolide erythromycin inhibits protein synthesis and resistance is induced by N -dimethyl-ation of adenine within the 23S rRNA, which results in reduced affinity of ribosomes for antibiotics related to erythromcin (Skinner et al. 1983). Sulfonamides function by binding tightly to chromosomal dihydropteroate synthetase and resistance to sulfonamides is developed in the resistance plasmid through a form of the enzyme that is resistant to the effect of sulfonamides. 

Macrolides Erythromycin Inhibits protein synthesis by binding Gram-positive cocci, mycoplasma,... 

Newer and more generally usefnl macrolide antibiotics include azithromycin (Zithromax) and clarithromycin (Biaxin). These too are wide-spectrum antibiotics and both are semisynthetic derivatives of erythromycin. Like the tetracyclines, the macrolide antibiotics act as protein synthesis inhibitors and also do so by binding specifically to the bacterial ribosome, thongh at a site distinct from that of the tetracyclines. 

The macrolides are orally absorbed but they are acid-labile. They therefore need to be administered in acid-resistant capsules or as acid-resistant esters. The macrolides are widely distributed into all fluids except the CNS. Protein binding is about 90%. They are eliminated via biliary excretion with extensive enterohepatic circulation. Elimination half-lives vary from 1.4 h for erythromycin to 40-60 h for azithromycin. 

Cethromycin (ABT-773) 39 (Advanced Life Sciences) had an NDA filed in October 2008 for the treatment of CAP.67 Advanced Life Sciences is also evaluating cethromycin 39 against other respiratory tract infections and in pre-clinical studies as a prophylactic treatment of anthrax post-exposure. Cethromycin 3968 70 is a semi-synthetic ketolide derivative of erythromycin 4071 originally synthesised by Abbott Laboratories,72 which like erythromycin 40, inhibits bacterial protein synthesis through binding to the peptidyl-transferase site of the bacterial 50S ribosomal subunit. Important macrolide antibiotics in clinical use today include erythromycin 40 itself, clarithromycin, azithromycin and, most recently, telithromycin (launched in 2001). 

Macrolides, particularly erythromycin and clarithromycin, inhibit CYP3A4. With erythromycin, the inhibition of CYP3A4 is non-competitive due to irreversible binding with the isoenzyme to form an inactive complex. Thus, unlike the case with inhibitors with a short half-life (e.g. cimetidine), the offset of inhibition is slow since new enzyme must be synthesized to replace the inactive complexes. Azithromycin, clarithromycin and erythromycin can prolong the Q-T interval and must not be co-administered with other Q-T-prolonging drugs. 

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