What are Macrolides Antibiotics?

Macrolides, alongside β-lactams, are among the most therapeutically relevant and extensively prescribed medications around the globe. They are employed for the treatment of bacterial infections that are classified as either Gram-positive or Gram-negative. During the COVID-19 pandemic, the use of macrolide antibiotics was greatly increased due to their efficacy in treating community-acquired respiratory tract infections, anti-inflammatory and immunomodulatory properties.

It has been reported that macrolide antibiotics have a wide range of potential immunomodulatory effects. These include the ability to down-regulate prolonged inflammation, the reduction of airway mucus secretion, the inhibition of bacterial biofilm, the reduction of reactive oxygen species production, the inhibition of neutrophil activation and mobilization, the acceleration of neutrophil apoptosis, and the blocking of nuclear transcription factor activation. Macrolides were found to initially decrease, then increase, and finally have a sustained suppression of cytokine secretions from normal human bronchial epithelial cells. This suppression was achieved through the inhibition and activation of extracellular signal-regulated kinases (ERK). Additionally, macrolides were found to reversibly retard cell proliferation, most likely through ERK interaction. In line with this, macrolide antibiotics may influence the formation of mucin as well as the migration of neutrophils by interfering with the ERK signal transduction pathway.

Chemical structures of macrolide antibiotics. (Paul D., et al., 2023)

Macrolide antibiotics mechanism of action

Macrolide antibiotics attach to the ribosome in the nascent peptide exit tunnel (NPET), which is a tiny passage that the polypeptides formed in the peptidyl transferase center (PTC) travel through as they escape the ribosome. The presence of a macrolide molecule in the NPET, located close to the PTC, hinders the movement of the newly formed peptides. Exposing delicate cells to macrolide antibiotics results in a fast decrease in the overall production of proteins and the buildup of peptidyl-tRNA. These medicines were demonstrated to hinder the production of model polypeptides and induce premature peptidyl-tRNA drop-off in the cell-free translation system. These discoveries led to the widespread assumption that macrolides hinder the formation of all cellular polypeptides by inhibiting the release of the newly formed chain and halting translation in its early stages.

Recent data indicates that macrolides specifically hinder the process of translating certain cellular proteins. This inhibition is very dependent on both the sequence of the newly formed protein and the structure of the antibiotic. Thus, macrolides are identified as agents that regulate translation rather than acting as broad inhibitors of protein synthesis.

Macrolide antibiotics at BOC Sciences

Macrolide antibiotics uses

The following graphics provide a summary of the pharmacokinetic parameters for azithromycin, clarithromycin, dirithromycin, and roxithromycin when administered in numerous doses. The macrolides have a higher resistance to acid, which results in an increase in their bioavailability. When compared to plasma concentrations, the macrolide antibiotics can attain greater tissue concentrations. These antibiotics are able to infiltrate the tissues of the respiratory system, tonsils, and prostate, as well as polymorphonuclear leukocytes, with remarkable success. There is a wide range of values for protein binding, from 7 to 90%. Instead of albumin, macrolides possess the ability to bind alpha-1-acid glycoprotein. It is not clear what the relevance of such protein binding is. There are several benefits associated with the more recent macrolides, including a longer half-life, improved bioavailability, and enhanced tissue penetration.

Steady-State Pharmacokinetic Values for Macrolides. (Jain R., et al., 2004)

Maximum Tissue and Fluid Concentrations for Macrolides. (Jain R., et al., 2004)

Types of Macrolide antibiotics

Macrolides are among the antibiotics that are used the most regularly, with azithromycin being the most commonly prescribed antibiotic in several nations all over the world. Macrolides are categorized according to the macro-lactone skeleton that they possess, and they can have either 14-, 15-, or 16-membered rings.

Macrolides have a wide range of antibacterial action against several gram positive and gram negative microorganisms. Macrolide antibiotics are commonly prescribed to treat respiratory, vaginal, gastrointestinal, and skin/soft tissue infections caused by susceptible organisms. Erythromycin specifically targets and is effective against several bacteria including S. pyogenes, S. pneumoniae, susceptible S. aureus, susceptible H. influenzae, Listeria monocytogenes, Moraxella catarrhalis, Campylobacter jejuni, Neisseria gonorrhoeae, Chlamydia trachomatis, Bordetella pertussis, and various anaerobic bacteria such as Propionibacterium acnes. In addition, they demonstrate efficacy against intracellular pathogens such as C. pneumoniae, L. pneumophilia, M. pneumoniae, H. pylori, and U. urealyticum.

• Clarithromycin exhibits greater efficacy against S. aureus, S. pyogenes, and S. pneumoniae compared to erythromycin. It has enhanced efficacy against intracellular pathogens such as C. pneumoniae, C. trachomatis, H. pylori, and L. pneumophilia in comparison to erythromycin. Clarithromycin exhibits comparable efficacy against H. influenzae as erythromycin, but, the main metabolite of clarithromycin (14-OH Clarithromycin) demonstrates superior action. Clarithromycin has demonstrated comparable efficacy against N. gonorrheae when compared to erythromycin.
• Azithromycin has reduced efficacy against gram positive organisms, while demonstrating enhanced efficacy against gram-negative organisms in comparison to erythromycin and clarithromycin. For instance, azithromycin has enhanced efficacy (2-8 times more potent) against H. influenzae, H. parainfluenzae, N. gonorrheae, L. pneumonophilia, and M. catarrhalis in comparison to erythromycin. Additionally, it has enhanced efficacy against Enterobacteriaceae, such as Escherichia, Salmonella, Shigella, and Yersinia species, in comparison to erythromycin. Azithromycin, similar to clarithromycin, has enhanced efficacy against C.pneumoniae and M.pneumoniae.
• Dirithromycin exhibits lower efficacy against gram positive pathogens in comparison to erythromycin. Furthermore, its efficacy against H.influenzae is lower, however it has superior efficacy against C.jejuni compared to erythromycin. Like other macrolides, dirithromycin does not have activity against Enterobacteriaceae and Pseudomonas species. Dirithromycin has activity against Legionella, Chlamydia, and Mycoplasma species that are causative agents of respiratory illnesses.
• Roxithromycin has the lowest level of activity among the 14-membered macrolides. It is effective against both gram-positive and gram-negative cocci, as well as gram-positive bacilli and some gram-negative bacilli. Roxithromycin has lower potency compared to erythromycin against susceptible staphylococci and streptococci. Roxithromycin exhibits comparable efficacy against Legionella species, but demonstrates up to a four-fold decrease in activity against H. influenzae and M. catarrhalis. The efficacy of this substance against some bacteria that affect the urinary and genital systems, such as N.gonorrheae and C. trachomatis, is roughly comparable to that of erythromycin. Roxithromycin exhibits significant efficacy against atypical pathogens, including Mycobacterium avium complex, Helicobacter pylori, and Borrelia spp.

Spectrum of activity of different macrolide antibiotics. (Paul D., et al., 2023)

Reference

1. Paul D., et al., Antibiotic Potentiation as a Promising Strategy to Combat Macrolide Resistance in Bacterial Pathogens, Antibiotics, 2023, 12(12): 1715.
2. Shinkai M., et al., Macrolide antibiotics as immunomodulatory medications: proposed mechanisms of action, Pharmacology & therapeutics, 2008, 117(3): 393-405.
3. Vázquez-Laslop N., et al., How macrolide antibiotics work, Trends in biochemical sciences, 2018, 43(9): 668-684.
4. Jain R., et al., The macrolide antibiotics: a pharmacokinetic and pharmacodynamic overview, Current pharmaceutical design, 2004, 10(25): 3045-3053.