Incorporating Single-Copper Sites and Host Defense Peptides into a Nanoreactor for Antibacterial Therapy by Bioinspired Design

A sustainable solution to the dramatic spread of antibiotic resistance threatening public health security is the development of antibiotic-free antimicrobial substances. Inspired by natural host defense mechanisms involving amino-terminal copper–nickel binding motif (ATCUN) antimicrobial peptides (AMPs), we have designed and prepared an artificial complex (Cu@G-AMPs) incorporating single-atom Cu catalysts for antibacterial therapy. The substrate of the complex, formed from guanine doped with abundant heteroatoms, anchored single Cu atoms with a coordination number of 2 and an average bond length of 1.91 Å. Interestingly, Cu@G-AMPs, exhibiting Fenton-like catalytic activity, caused the inactivation of methicillin-resistant Staphylococcus aureus (MRSA) by generating and delivering reactive oxygen species (ROS) cargo. Mechanistically, the intrinsic stress response system of MRSA underwent an irreversible collapse when Cu@G-AMPs initiated its offensive program associated with non-specific targets. Furthermore, Cu@G-AMPs, which inherited the immunomodulatory properties of AMPs, sequentially carried out the functions of pulling edge closure, stabilizing granulation tissue, promoting collagen fiber proliferation, alleviating inflammation, and promoting neovascularization in wound areas infected by MRSA. Our results show that Cu@G-AMPs will provide a new perspective on untangling the complex regulatory networks that resistant bacteria have cultivated to deactivate commercial antibiotics.