Abstract:　Infections　caused　by　pathogens　can　be　a　significant　challenge　in　wound　healing,　particularly　when　antimicrobial　resistance　is　a　factor.　This　can　pose　a　serious　threat　to　human　health　and　well-being.　In　this　scenario,　it　is　imperative　to　explore　novel　antimicrobial　agents　to　fight　against　multi-drug　resistant　(MDR)　pathogenic　bacteria.　This　study　employed　rational　design　strategies,　including　truncation,　amino　acid　replacement,　and　heterozygosity,　to　obtain　seven　α-helical,　cationic,　and　engineered　peptides　based　on　the　original　template　of　Abhisin.　Among　the　analogs　of　Abhisin,　AB7　displayed　broad-spectrum　and　potent　antimicrobial　activity,　superior　targeting　of　membranes　and　DNA,　and　the　ability　to　disrupt　biofilms　and　anti-endotoxins　in　vitro.　Additionally,　we　evaluated　the　anti-infection　ability　of　AB7　using　a　murine　skin　wound　model　infected　with　methicillin-resistant　Staphylococcus　aureus　(MRSA)　and　found　that　AB7　displayed　negligible　toxicity　both　in　vitro　and　in　vivo.　Furthermore,　AB7　exhibited　desirable　therapeutic　efficacy　by　reducing　bacterial　burden　and　pro-inflammatory　mediators,　modulating　cytokines,　promoting　wound　healing,　and　enhancing　angiogenesis.　These　results　highlight　the　potential　of　AB7　as　a　promising　candidate　for　a　new　antibiotic.　Key　points:　•　A　α-helical,　cationic,　and　engineered　peptide　AB7　was　obtained　based　on　Abhisin.　•　AB7　exhibited　potent　antimicrobial　activity　and　multiple　bactericidal　actions.　•　AB7　effectively　treated　infected　skin　wounds　in　mice.　Graphical　Abstract:　[Figure　not　available:　see　fulltext.].　©　2023,　The　Author(s),　under　exclusive　licence　to　Springer-Verlag　GmbH　Germany,　part　of　Springer　Nature.