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

Abstract

The expression of β-lactamase, particularly metallo-β-lactamase (MBL) in bacteria has caused significant resistance to clinically important β-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-causative β-lactamase. Further investigations demonstrate this β-lactamase-activatable 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 by β-lactamase-expressing pathogenic bacteria.