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An amphipathic and cationic antimicrobial peptide kills colistin resistant Gram-negative pathogens in vivo

By Thomas T. Thomsen, Mette Kolpen, Vinoth Wigneswaran, Ulrik Kromann, Anna Ebbensgaard, Anette M. Hammerum, Henrik Hasman, Stine Radmer, Kasper N Kragh, Rasmus Hartmann-Petersen, Paul Robert Hansen, Anders Folkesson, Niels Frimodt-Møller, Anders Løbner-Olesen

Posted 13 Dec 2021
bioRxiv DOI: 10.1101/2021.12.13.472350

New antibiotics are needed against multidrug resistant Gram-negative pathogens that have compromised global health systems. Antimicrobial peptides are generally considered promising lead candidates for the next generation of antibiotics but have not fulfilled this expectation. Here we demonstrate activity of a cationic amphipathic undecapeptide (ChIP; Charge change Independent Peptide) against a wide panel of multidrug resistant Gram-negative pathogens. Importantly, the antimicrobial activity of ChIP is independent of the surface charge changes that confer colistin resistance through modification of Lipid A, while decreased activity of ChIP correlates with GlcN1 tri-acylation of Lipid A. In an in vivo peritonitis mouse model ChIP displays excellent activity against both colistin sensitive and resistant Escherichia coli and Acinetobacter baumannii strains.

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