Mode of Action of Macrolides

Although the study on mode of action of macrolides dates back to late 1950s but it is still ambiguous. These compounds bind to the 50S subunit of ribosomes present in prokaryotes with a specific target in the 23S ribosomal RNA molecule and in varied proteins of ribosomes. Earliest studies suggested that 14- and 16-membered macrolides exerted different inhibitory effects on the elongation phase of bacterial protein synthesis. In one hand, the 16-membered compounds inhibit peptidyl transferase reactions whereas the 14-membered compounds inhibits the translocation of peptidyl-tRNA on the other. More recently a hypothesis suggests that all macrolides stimulates dissociation of peptidyl-tRNA from the ribosome during the elongation phase that leads to inhibition of protein synthesis. 

This information has been adapted from the conclusion portion of following paper. Go through all the references of the paper used. 

Mazzei, T., Mini, E., Noveffi, A., & Periti, P. (1993). Chemistry and mode of action of macrolides Journal of Antimicrobial Chemotherapy. 1–9.

Macrolides are a class of antibiotics that inhibit bacterial protein synthesis by binding to the 50S ribosomal subunit. This action prevents the elongation of polypeptide chains during protein synthesis, ultimately leading to inhibition of bacterial growth and reproduction. Here's a detailed explanation of the mode of action of macrolides:

1. Binding to Ribosome: Macrolides bind reversibly to the 50S ribosomal subunit of bacterial ribosomes. Specifically, they bind to a region of the ribosome known as the 23S rRNA.

2. Inhibition of Translocation: Once bound to the ribosome, macrolides prevent the translocation of tRNA from the A-site to the P-site during translation. This inhibits the elongation of the nascent polypeptide chain, interrupting the process of protein synthesis.

3. Peptide Bond Formation: Macrolides also interfere with the formation of peptide bonds between amino acids. By blocking the formation of peptide bonds, they prevent the addition of new amino acids to the growing polypeptide chain.

4. Ribosome Stalling: The binding of macrolides to the ribosome induces conformational changes in the ribosomal structure, leading to ribosome stalling. This further disrupts the progression of translation and inhibits the synthesis of functional proteins.

5. Bacteriostatic Effect: Macrolides generally exhibit a bacteriostatic effect, meaning they inhibit bacterial growth rather than causing bacterial cell death (bactericidal effect). However, in some cases and at higher concentrations, they may exhibit a bactericidal effect.

6. Post-antibiotic Effect: Macrolides may also exert a post-antibiotic effect, where bacterial growth remains suppressed even after the antibiotic concentration has fallen below the minimum inhibitory concentration (MIC). This effect contributes to the overall efficacy of macrolides in treating bacterial infections.

7. Spectrum of Activity: Macrolides are effective against a wide range of Gram-positive and some Gram-negative bacteria. They are particularly active against respiratory pathogens such as Streptococcus pneumoniae, Haemophilus influenzae, and atypical bacteria like Mycoplasma pneumoniae and Legionella pneumophila.

In summary, macrolides inhibit bacterial protein synthesis by binding to the 50S ribosomal subunit, interfering with translocation and peptide bond formation, ultimately leading to inhibition of bacterial growth. Their broad spectrum of activity and favourable pharmacokinetic properties make them valuable antibiotics for the treatment of various bacterial infections.