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However, the development of new antibiotics has stagnated in recent years, highlighted the critical need for the discovery of innovative antimicrobial agents. This study aims to evaluate the antibacterial activity of naphthoquinones derived from <jats:italic>Arnebia euchroma<\/jats:italic> (Royle) Johnst (ADNs) and elucidate their underlying mechanisms. The antibacterial efficacy of ADNs was assessed using the microbroth dilution method. The antibacterial mechanism of acetylshikonin (ASK) was further explored through scanning electron microscopy, RNA\u2010Seq and transcriptomic analysis, fluorescent probes, high\u2010performance liquid chromatography, qRT\u2010PCR and molecular docking. The results demonstrated that all the ADNs exhibit potent antibacterial activity against MDR Gram\u2010positive pathogens, including methicillin\u2010resistant <jats:styled-content style=\"fixed-case\">\n<jats:italic>Staphylococcus aureus<\/jats:italic>\n<\/jats:styled-content> (MRSA), vancomycin\u2010resistant <jats:italic>Enterococcus<\/jats:italic>, and linezolid\u2010resistant <jats:italic>Enterococcus<\/jats:italic>. Notably, ASK showed minimum inhibitory concentration of 1\u20132\u2009\u03bcg\/mL against MRSA. Mechanistic investigations revealed that ASK operates through a multifaceted antibacterial mechanism. First, ASK disrupts bacterial membrane integrity and dissipates proton motive force by targeting membrane phospholipids. Further analysis demonstrated a significant reduction in oxygen consumption and ATP production, indicative of respiratory chain inhibition. Additionally, ASK interferes with bacterial cell wall synthesis, as evidenced by reduction of peptidoglycan precursors and downregulated expression of genes involved in peptidoglycan synthesis. In conclusion, ASK represents a promising antimicrobial agent with potential efficacy against infections caused by MDR Gram\u2010positive bacteria and offers valuable insights for the development of novel therapeutic strategies.<\/jats:p>","DOI":"10.1002\/ptr.8427","type":"journal-article","created":{"date-parts":[[2025,1,7]],"date-time":"2025-01-07T10:07:12Z","timestamp":1736244432000},"page":"1372-1387","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Acetylshikonin Derived From <i>Arnebia euchroma<\/i> (Royle) Johnst Kills Multidrug\u2010Resistant Gram\u2010Positive Pathogens In\u00a0Vitro and In\u00a0Vivo"],"prefix":"10.1002","volume":"39","author":[{"given":"Xia","family":"Xiao","sequence":"first","affiliation":[{"name":"College of Veterinary Medicine Yangzhou University  Yangzhou China"},{"name":"Jiangsu Co\u2010Innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses 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