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Non-antibiotic therapies could serve as important countermeasures to control MDR<jats:italic>Salmonella<\/jats:italic>outbreaks. In this study, antimicrobial activity of cationic \u03b1-helical bovine NK-lysin-derived antimicrobial peptides was evaluated against MDR<jats:italic>Salmonella<\/jats:italic>outbreak isolates. NK2A and NK2B strongly inhibited MDR<jats:italic>Salmonella<\/jats:italic>growth while NK1 and NK2C showed minimum-to-no growth inhibition. Scrambled-NK2A, which is devoid of \u03b1-helicity but has the same net positive charge as NK2A, also failed to inhibit bacterial growth. Incubation of negatively charged MDR<jats:italic>Salmonella<\/jats:italic>with NK2A showed increased Zeta potential, indicating bacterial-peptide electrostatic attraction. Confocal and transmission electron microscopy studies revealed NK2A-mediated damage to MDR<jats:italic>Salmonella<\/jats:italic>membranes. LPS inhibited NK2A-mediated growth suppression in a dose-dependent response, suggesting irreversible NK2A-LPS binding. LPS-NK2A binding and bacterial membrane disruption was also confirmed via electron microscopy using gold nanoparticle-NK2A conjugates. Finally, NK2A-loaded polyanhydride nanoparticles showed sustained peptide delivery and anti-bacterial activity. Together, these findings indicate that NK2A \u03b1-helicity and positive charge are prerequisites for antimicrobial activity and that MDR<jats:italic>Salmonella<\/jats:italic>killing is mediated by direct interaction of NK2A with LPS and the inner membrane, leading to bacterial membrane permeabilization. With further optimization using nano-carriers, NK2A has the potential to become a potent anti-MDR<jats:italic>Salmonella<\/jats:italic>agent.<\/jats:p>","DOI":"10.1038\/s41598-021-98860-6","type":"journal-article","created":{"date-parts":[[2021,9,29]],"date-time":"2021-09-29T10:21:04Z","timestamp":1632910864000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Bovine NK-lysin peptides exert potent antimicrobial activity against multidrug-resistant Salmonella outbreak isolates"],"prefix":"10.1038","volume":"11","author":[{"given":"Rohana P.","family":"Dassanayake","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Briony M.","family":"Atkinson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adam S.","family":"Mullis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shollie M.","family":"Falkenberg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric M.","family":"Nicholson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eduardo","family":"Casas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Balaji","family":"Narasimhan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shawn M. 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