Therapeutic Areas II: Cancer, Infectious Diseases, Inflammation & Immunology and Dermatology
T. Kaneko, ... T.V. Magee, in Comprehensive Medicinal Chemistry II, 2007
Macrolide antibiotics such as erythromycin, clarithromycin, and azithromycin have been used widely to combat primarily respiratory diseases caused by Gram-positive pathogens and fastidious Gram-negative pathogens. The popularity of this class of antibiotics is largely due to their spectrum of activity and their relative safety. The second-generation macrolides, clarithromycin and azithromycin, are derived from erythromycin, and have a broader spectrum of activity and improved pharmacokinetic properties. Macrolide antibiotics inhibit bacterial protein synthesis by interfering with ribosome function, and details of the inhibitory mechanisms have been clarified by recent advances in the x-ray structure of the ribosome–macrolide complexes. The widespread use of these antibiotics had catalyzed the emergence of macrolide-resistant strains, especially among Streptococcus pneumoniae, Streptococcus pyogenes, and Staphylococcus aureus. In response to these resistant pathogens, third-generation macrolides, represented by the ketolide telithromycin, are being developed. These derivatives have increased affinity for the bacterial ribosome and a reduced propensity to be efflux pump substrates compared with the first- and second-generation macrolides. Discovery of telithromycin and its introduction into the market triggered a renewed interest in the chemistry of macrolide antibiotics in recent years. As a result, a large number of novel and potent analogs were synthesized and are under investigation. In this chapter, the major classes of macrolide antibiotics as well as the newer analogs are reviewed. Included are descriptions of their syntheses, their mechanism of action, resistance mechanisms, structure–activity relationship (SAR), and their pharmacokinetic and safety properties.