Although several new antibiotic candidates are in the clinical pipeline, the future evolution of resistance in bacteria may render them ineffective. This project aims to develop a framework for forecasting the long-term effectiveness of new antibiotic candidates. For this purpose, we will decipher the general principles shaping bacterial resistance to a wide range of antibiotic candidates currently in development. Using recently developed methods in our laboratory, we will study resistance evolution in bacterial ESKAPE pathogens at unprecedented resolution and address four specific aims. First, we explore the shared features of antibiotics with limited susceptibility to resistance. Second, we systematically map species-specific differences in resistance evolution with implications on narrow-spectrum antibacterial therapies that could remain effective. Third, we assess the clinical risks associated with resistance by studying the global biogeography and habitat-specificity of resistant bacteria. Finally, we systematically explore the potential links between resistance evolution and increased bacterial virulence. The outcomes will provide guidelines for future antibiotic use, aid in genomic surveillance of resistance genes, and facilitate the design of antibiotics with reduced susceptibility to resistance.