Selective inhibition of resistant bacterial pathogens using a β-lactamase-activatable antimicrobial peptide with significantly reduced cytotoxicity

The expression ofβ-lactamase,particularly metallo-β-lactamase(MBL)in bacteria has caused significant resistance to clinically importantβ-lactam antibiotics,including life-saving carbapenems.Antimicrobial peptides(AMPs)have emerged as promising therapeutic agents to combat antibiotic resistance.However,the cytotoxic AMPs has been one of the major concerns for their applications in clinical practice.Herein,we report a novel cephalosporin-caged AMP,which shows significantly reduced cytotoxicity,hemolytic activity,and antibacterial activity but turns highly active against bacteria upon specific hydrolysis by the antimicrobial resistance-causativeβ-lactamase.Further investigations demonstrate thisβ-lactamaseactivatable AMP selectively inactivates resistant bacterial pathogens over susceptible bacteria.This strategy should be applicable to other AMPs as a potential solution for the treatment of infectious diseases caused byβ-lactamase-expressing pathogenic bacteria.