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.　©　2024　THE　AUTHORS