A novel series of acylides 4 were designed to overcome antibacterial resistance and evaluated for in vitro and in vivo activity. This series of acylides was designed from clarithromycin by changing the substitution on the desosamine nitrogen, followed by conversion to 3-O-acyl and 11,12-carbamate. These compounds showed significantly potent antibacterial activity against not only Gram-positive pathogens, including macrolide-lincosamide-streptogramin B (MLS(B))-resistant and efflux-resistant strains, but also Gram-negative pathogens such as Haemophilus influenzae. These acylides also showed better activity against telithromycin resistant Streptococcus pneumoniae strains.