Bacterial resistance to antibiotic treatment has become a global health problem, particularly among major respiratory tract pathogens. To address this, a novel series of 6-O-substituted ketolides active against both MLSB- and efflux-resistant bacteria was designed and synthesized. Structure-activity relationship (SAR) studies led to the discovery of ABT-773, a potent antibacterial agent. ABT-773 exhibited excellent activities against all key respiratory tract pathogens, including those resistant to macrolides and other antibiotics. It was highly active against the two major types of resistance: MLSB resistance encoded by erm genes and efflux resistance encoded by mef genes. ABT-773 demonstrated excellent efficacies against various infections in experimental animal models. Compared to reference macrolide azithromycin and reference ketolide telithromycin, ABT-773 showed improved efficacy against infections caused by macrolide-susceptible bacteria and excellent efficacy against macrolide-resistant bacteria, while telithromycin showed weaker efficacy and azithromycin showed weaker or no efficacy against such resistant infections.