Macrolide Antibiotics

Abstract

Macrolide antibiotics are one of the larger classes of fermentation‐derived natural products. In addition, many semisynthetic derivatives have been synthesized. They treat infections caused by most Gram‐positive bacteria, some susceptible Gram‐negative bacteria, and atypical bacteria such as Mycoplasma pneumoniae and Legionella pneumophila . They are orally bioavailable and accumulate in tissues and organs. They are regarded as one of the safest groups of antibiotics. Erythromycin is a 14‐membered ring macrolide and foremost member of the class. First‐generation derivatives focused on deficiencies such as compound instability in acidic environments, bitter taste, low water solubility, low oral bioavailability, and gastrointestinal and cardiac side effects. Many of these problems were at least partly solved by first‐generation derivatives such as esters and salts that made the active entities less prone to degradation. Second‐generation derivatives chemically changed substituents on the aglycone to stabilize it from intramolecular decomposition. This group includes clarithromycin and azithromycin that have become the most important macrolides to date. The problem of bacterial resistance to antibiotics was elegantly addressed by the ketolides. Telithromycin (Ketek®) was the first ketolide (third generation of erythromycin derivatives) to be approved and marketed, but postmarketing surveillance uncovered side effects and its use has been restricted. Macrolides are also important veterinary antibiotics and three new agents have been developed. Studies have continued to search for new agents using combinatorial biosynthesis, but the generation of large numbers of novel polyketides remains unfulfilled at this time.