Selective inhibition of resistant bacterial pathogens using a ,B-lactamase-activatable antimicrobial peptide with significantly re duce d cytotoxicity

The expression of ,B-lactamase, particularly metallo- ,B-lactamase (MBL) in bacteria has caused significant resistance to clinically important ,B-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 ,B-lactamase. Further investigations demonstrate this ,B-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 by ,B-lactamase-expressing pathogenic bacteria. (c) 2023 Published by Elsevier B.V. on behalf of Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences.

Automated summary

The expression of B-lactamase in bacteria has led to significant resistance to clinically important B-lactam antibiotics. Antimicrobial peptides (AMPs) have emerged as potential therapeutic agents to combat antibiotic resistance, but their cytotoxicity has been a major concern. This study reports a novel cephalosporin-caged AMP that shows reduced cytotoxicity and hemolytic activity, but becomes highly active against bacteria upon specific hydrolysis by antimicrobial resistance-causing B-lactamase. Further investigations demonstrate that this B-lactamase-activatable AMP selectively inactivates resistant bacterial pathogens. This strategy could be applicable to other AMPs for the treatment of infectious diseases caused by B-lactamase-expressing pathogenic bacteria.