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We developed a novel antimicrobial peptide, Pam-3, with antibacterial and antibiofilm properties to counter this threat. The peptide is based on an eight-amino acid carboxyl-terminal fragment of human \u03b2-defensin 1. Pam-3 exhibited prominent antimicrobial activity against multidrug-resistant ESKAPE pathogens and additionally eradicated already established biofilms in vitro, primarily by disrupting membrane integrity of its target cell. Importantly, prolonged exposure did not result in drug-resistance to Pam-3. In mouse models, Pam-3 selectively reduced acute intestinal <jats:italic>Salmonella<\/jats:italic> and established <jats:italic>Citrobacter<\/jats:italic> infections, without compromising the core microbiota, hence displaying an added benefit to traditional broad-spectrum antibiotics. 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