Novel erythromycin derivatives with aryl groups tethered to the C-6 position are potent protein synthesis inhibitors and active against multidrug-resistant respiratory pathogens

A novel series of erythromycin derivatives has been discovered with potent activity against key respiratory pathogens, including those resistant to er ythromycin. These compounds are characterized by having an aryl group tethe red to the C-6 position of the erythronolide skeleton. Extensive structural modification of the C-6 moiety led to the discovery of several promising c ompounds with potent activity against both mef- and erm-mediated resistant Streptoccoccus pneumoniae. Preliminary mechanistic studies indicated that t he new macrolides are potent protein synthesis inhibitors, which interact w ith methylated ribosomes isolated from resistant organisms. In experimental animal models, these compounds exhibited excellent in vivo efficacy and ba lanced pharmacokinetic profiles.