Macrolide Antibiotics and Antibacterial Activity

Macrolide antibiotics are characterised by a large macrocyclic lactone ring to which one or more deoxy sugars are attached. Since the 1950s, this class has evolved from erythromycin to second-generation agents such as clarithromycin and azithromycin, and more recently to ketolides and fluoroketolides. Their principal mode of action is to bind the bacterial 50S ribosomal subunit, obstructing the nascent peptide exit tunnel and thereby halting protein synthesis. Macrolides exhibit potent activity against many Gram-positive cocci, atypical pathogens such as Mycoplasma and Chlamydia, and, to a lesser extent, certain Gram-negative species. Widespread clinical use has given rise to resistance mechanisms including methylation of adenine residues in 23S rRNA, point mutations in ribosomal RNA, and active efflux. In response, medicinal chemistry efforts have focused on scaffold modification, sugar replacement and hybrid architectures to improve binding affinity, evade resistance determinants and broaden the antibacterial spectrum. In addition to direct antimicrobial effects, macrolides possess immunomodulatory properties, attenuating excessive inflammatory responses in chronic airway diseases. Ongoing research seeks to balance efficacy, safety and pharmacokinetic profiles while addressing the urgent global challenge of antibiotic resistance.

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Macrolide Antibiotics and Antibacterial Activity publication trend

The graph below shows the total number of articles in macrolide antibiotics and antibacterial activity across all publications each year (not limited to Nature Index journals).

Technical terms

Macrocyclic lactone: A large ring of 12–16 atoms forming the core of macrolide antibiotics to which sugar residues are attached.

Ketolide: A subclass of macrolides in which the cladinose sugar is replaced by a keto function, enhancing binding to mutated ribosomal sites.

50S ribosomal subunit: The larger subunit of the bacterial ribosome where macrolides bind to block peptide elongation.

rRNA methylation: The enzymatic addition of methyl groups to specific adenine residues in 23S ribosomal RNA, a common mechanism of macrolide resistance.

Efflux pump: A membrane protein complex that actively exports antibiotics out of bacterial cells, reducing intracellular drug concentration.

References

1. Synthetic macrolides overcoming MLSBK-resistant pathogens. Cell Discovery (2024).
2. Design, Synthesis and Biological Evaluation of Conjugates of 3-O-Descladinose-azithromycin and Nucleobases against rRNA A2058G- or A2059G-Mutated Strains. Molecules (2023).
3. Computational Studies on Selected Macrolides Active against Escherichia coli Combined with the NMR Study of Tylosin A in Deuterated Chloroform. Molecules (2022).
4. Macrolide Therapy in Chronic Inflammatory Diseases. Mediators of Inflammation (2012).