Caister Academic Press

Use of Antibiotic Core Structures to Generate New and Useful Macrolide Antibiotics

Prabhavathi Fernandes
from: Antibiotics: Current Innovations and Future Trends (Edited by: Sergio Sánchez and Arnold L. Demain). Caister Academic Press, U.K. (2015) Pages: 375-394.


Macrolides, such as erythromycin, are safe and effective antibiotics that are broadly used in adults and children. Clarithromycin and azithromycin were introduced in the 1990s and became popular because of improved gastrointestinal tolerability and pharmacokinetics but they exhibit cross resistance with erythromycin. Intense efforts in many pharmaceutical companies led to the third-generation macrolide, telithromycin, a 3-keto aglycone of clarithromycin with an extended 11, 12-carbamate side chain. Telithromycin was invented using two lessons learned from older macrolides:(i) additional side chains on the macrolide ring, as found on 16-membered macrolides, can gain activity against resistant organisms, and (ii) an aglycone with a keto group as noted in picromycin, instead of erythromycin's cladinose can retain antibacterial activity. Although active against drug-resistant bacteria, telithromycin failed in the clinic due to serious adverse events. Solithromycin is a fourth generation macrolide, a fluoroketolide, in late stage development that is differentiated from telithromycin in lacking the latter's pyridine containing side chain, which interacts with human nicotinic acetylcholine receptors to produce treatment-limiting side effects, and in having a third binding region in the bacterial ribosome to help overcome resistance. Solithromycin is in late-stage clinical development. Molecular mode of action studies could lead to even more potent molecules in the future, perhaps with uses beyond antiinfectives read more ...
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