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TZP4 showed potent antimicrobial activity comparable to melittin against antibiotic\u2010resistant bacteria, such as methicillin\u2010resistant <jats:italic>Staphylococcus aureus<\/jats:italic> and multidrug\u2010resistant <jats:italic>Pseudomonas aeruginosa<\/jats:italic>. TZP4 showed high resistance to proteolytic degradation and low tendency to develop drug resistance. The results from membrane depolarization, SYTOX Green uptake, flow cytometry, and gel retardation revealed that the mechanism of antimicrobial action of TZP4 involved an intracellular target rather than the bacterial cell membrane. Furthermore, TZP4 suppressed the messenger RNA levels of inducible nitric oxide synthase and tumor necrosis factor\u2010\u03b1 (TNF\u2010\u03b1) and inhibited the release of nitric oxide and TNF\u2010\u03b1 in lipopolysaccharide (LPS)\u2010stimulated RAW264.7 cells. BODIPY\u2010TR\u2010cadaverine displacement and dissociation of fluorescein isothiocyanate (FITC)\u2010labeled LPS assays revealed that TZP4 strongly bound to LPS and disaggregated the LPS oligomers. Flow cytometric analysis demonstrated that TZP4 inhibits the binding of FITC\u2010conjugated LPS to RAW264.7 cells. These observations indicate that TZP4 may exert its antiendotoxic activity by directly binding with LPS and inhibiting the interaction between LPS and CD14<jats:sup>+<\/jats:sup> cells. Collectively, TZP4 is a promising drug candidate for the treatment of endotoxic shock and sepsis caused by Gram\u2010negative bacterial infections.<\/jats:p>","DOI":"10.1002\/bit.27499","type":"journal-article","created":{"date-parts":[[2020,7,14]],"date-time":"2020-07-14T12:05:56Z","timestamp":1594728356000},"page":"3508-3521","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Mechanisms of antimicrobial and antiendotoxin activities of a triazine\u2010based amphipathic polymer"],"prefix":"10.1002","volume":"117","author":[{"given":"Eun Young","family":"Kim","sequence":"first","affiliation":[{"name":"Department of Biomedical Science, Graduate School Chosun University Gwangju Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S. 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