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High prevalence of multidrug-resistant bacteria decreases effectiveness of conventional antibiotics and become severe threat to public health.New improvements in current methods or innovative therapeutic strategies are urgently needed to solve this problem.Antimicrobial peptides,known as host defense peptides,have been widely accepted as the first line to defend microbial infection effectively.However,low selectivity and high-cost are major impediment in its clinical applications.In this study,a novel derivative peptide (A-TH-PG) was produced by a γ-core—substituted design strategy.A-TH-PG not only retains the low toxicity of the advantages of the thanatin,but also reduces the synthesis costs.Properties of little hemolysis and relatively high stability in plasma were confirmed.A-TH-PG is highly effective against MRSE in vitro,and excellent in vivo therapeutic effects were also observed in a septicemic animal model.Combined mechanistic investigations through scanning and transmission electron microscopy and fluorescence assays,revealed that the killing of Methicillin-resistant Staphylococcus epidermidis (MRSE) was caused by disrupting cell division severely and damaging cell membranes.Furthermore,it is speculated that the disturbance of cell division may be a key biological action of A-TH-PG.Our results offer a feasible strategy for treating multidrug-resistant infections.