Conditional Antimicrobial Peptide Therapeutics

Antimicrobial peptides (AMPs) constitute a promis-ing class of alternatives to antibiotics to curb antimicrobial resistance. Nonetheless, their utility as a systemic agent is hampered by short circulation time and toxicity. Infection sites, analogous to tumors, harbor an aberrant microenvironment that has the potential to be exploited to develop conditionally activated therapeutics with an improved therapeutic index. In particular, we identified strategies to prolong systemic circulation of small, cationic AMPs in a mouse model of bacterial pneumonia. Specifically, we report an albumin-binding domain (ABD)-AMP conjugate as a long-circulating conditional AMP therapeutic with a masked activity that can be liberated by proteases in the infected tissue microenvironment. Our systemically administered conjugate enhanced the pulmonary delivery of active AMP while also reducing AMP exposure to other off-target organs. Importantly, this reduction in off-target exposure improved the safety profile of the AMP. The framework we present can be generalized to quantify and optimize the performance of this emerging class of conditional therapeutics.

Automated summary

Antimicrobial peptides (AMPs) have the potential to be an alternative to antibiotics for combating antimicrobial resistance, but their systemic application is hindered by short circulation time and toxicity. This study developed a strategy to prolong the systemic circulation of small cationic AMPs by conjugating them with an albumin-binding domain (ABD). The conjugate was able to enhance pulmonary delivery of the active AMP, while reducing exposure to other off-target organs, thereby improving safety. The framework presented in this study can be used to optimize the performance of this emerging class of conditional therapeutics.