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Methicillin-resistant Staphylococcus aureus (MRSA) has evolved to tolerate almost all known β-lactam antibiotics, and been exhibiting resistance to vancomycin. Developing new drugs against the MRSA infection are urgently needed. Natural resource is enriched with antimicrobial molecules. Here, we report an extract from leaves of Cyclocarya paliurus (ECPL), a species of tree native to China and being traditionally cultivated as medicinal plant, which shows a broad spectrum of bacteriostatic and bactericidal effects at MIC 50 15.99 ± 0.55 μg/ml against methicillin-susceptible and -resistant S. aureus. The ECPL suppresses bacterial expression of FtsZ at both transcriptional and protein levels, inhibits its GTPase activity, blocks the assembly dynamics of FtsZ, and disrupts the formation of Z-ring. The bacteria cells fail to divide, enlarge initially, and lyse eventually. In mouse model, the ECPL facilitates skin wound healing with MRSA infection as effective as vancomycin. Our study unveils the potential of identifying novel molecule in ECPL for development of new class of antibiotic against both methicillin-susceptible and -resistant S. aureus , and support domestication of the C. paliurus growing from wild to cultivated, and further scale up the cultivation into industrialized farm for sustainable harvest for pharmaceutic interest. [Display omitted] • An extract from Cyclocarya paliurus (ECPL) leaves shows anti-MRSA activity. • The ECPL suppresses bacterial FtsZ at transcriptional and protein levels and eliminates the GTPase enzyme activity. • Bacteria abort Z-ring formation , fail to divide, and die. • This effect bypasses known resistance machineries and shows a potential for new antibiotic development. • Domesticating and scaling up the cultivation will guaranty sustainable harvest for the pharmaceutic interest. [ABSTRACT FROM AUTHOR]