A β‐Lactamase Responsive Peptide Inhibits MRSA Infection through Self‐Assembled Nanonet

Abstract Gram‐positive S. aureus is one of the leading pathogens for death associated with antimicrobial resistance. The β‐lactamase (Bla) secreted by methicillin‐resistant S. aureus (MRSA) hydrolyzes nearly all β‐lactam antibiotics, leaving only a few antibiotics available for the clinical treatment of MRSA infections. Thereby, a Bla‐responsive peptide (BLAP) is designed here with the capacity of inhibiting MRSA infection through mimicking the host defense mechanism of human defensin‐6. The BLAP comprising a self‐assembling peptide sequence can respond specifically to the secreted Bla and assemble in situ surrounding MRSA. The assembled nanofibrous network is able to trap MRSA, preventing its invasion into the host cells effectively. As a consequence, the intramuscular injection of BLAP significantly restricted bacterial infection and abscess formation in mice. The biomimetic BLAP holds great potential for the efficient treatment of drug‐resistant gram‐positive bacterial infections.