Membrane-targeting antibiotics: recent developments outside the peptide space

The rise of antibiotic resistant bacteria requires unconventional strategies toward efficient chemotherapeutic agents, preferably with alternative mechanisms of action. The bacterial cell membrane has become an appealing target since its essential and highly conservative structure are key challenges to resistance mechanisms. Inspired by natural antimicrobial peptides, research on membrane-targeting antimicrobials has been growing out of the peptide space. The pursuit of more druggable molecules led to the discovery that the pharmacophore of antimicrobial peptides is smaller than anticipated. Several promising classes of membrane-targeting antimicrobials have been discovered, such as ceragenins, reutericyclines, carbohydrate amphiphiles - among others. This review will discuss the most recent findings on membrane-targeting antibiotics, focusing on small molecules outside the antimicrobial peptide molecular space.