Resistance to Macrolides, Lincosamides, and Streptogramins

The structurally unrelated antimicrobials, macrolides, lincosamides, and streptogramins are grouped into a single family, called MLS family. This classification is based on a similar, although not identical, mechanism of action. Macrolides are composed of a minimum of two amino and/or neutral sugars attached to a lactone ring of variable size [1] (Fig. 18.1). Erythromycin, produced by a strain of the actinomycete Saccharopolyspora erythraea (formerly Streptomyces erythraeus), is the first macrolide discovered in 1952. It actually corresponds to a mixture of antibiotics that includes erythromycin A, which is the active compound and has a 14-membered lactone ring with two sugars, cladinose and an amino sugar (e.g., desosamine). Other commercially available macrolides derived from erythromycin A include clarithromycin, dirithromycin, roxithromycin, as well as azithromycin that has an enlarged 15-membered ring resulting from a nitrogen insertion. Structural modifications of erythromycin A resulted in improved pharmacokinetic profiles and better tolerance, but cross-resistance between members of this class of antimicrobials was still observed. Some 16-membered ring macrolides are also available in a few countries (spiramycin, josamycin, midecamycin, and miocamycin) or for veterinary use (tylosin). The most recent class of ketolides comprises telithromycin and cethromycin (ABT-773), which are derived from clarithromycin and have two major modifications, replacement of cladinose by a keto-function and an 11-12-carbamate extension with an alkyl-aryl modification in telithromycin. The first fluoroketolide solithromycin (CEM-101), exhibiting a different side chain and a fluorine atom linked to C-2 of the lactone, shows higher in vitro activity and enhanced accumulation in macrophages as compared to telithromycin [2].