Antibacterial efficacy of an ultra-short palmitoylated random peptide mixture in mouse models of infection by carbapenem-resistant Klebsiella pneumoniae

Jonathan Z. Lau, Shanny Hsuan Kuo, Yael Belo, Einav Malach, Bar Maron, Hannah E. Caraway, Myung Whan Oh, Yi Zhang, Nahed Ismail, Gee W. Lau*, Zvi Hayouka*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Indiscriminate use of antibiotics has imposed a selective pressure for the rapid rise in bacterial resistance, creating an urgent need for novel therapeutics for managing bacterial infectious diseases while counteracting bacterial resistance. Carbapenem-resistant Klebsiella pneumoniae strains have become a major challenge in modern medicine due to their ability to cause an array of severe infections. Recently, we have shown that the 20-mer random peptide mixtures are effective therapeutics against three ESKAPEE pathogens. Here, we evaluated the toxicity, biodistribution, bioavailability, and efficacy of the ultra-short palmitoylated 5-mer phenylalanine:lysine (FK5P) random peptide mixtures against multiple clinical isolates of carbapenem-resistant K. pneumoniae and K. oxytoca. We demonstrate the FK5P rapidly and effectively killed various strains of K. pneumoniae, inhibited the formation of biofilms, and disrupted mature biofilms. FK5P displayed strong toxicity profiles both in vitro and in mice, with prolonged favorable biodistribution and a long half-life. Significantly, FK5P reduced the bacterial burden in mouse models of acute pneumonia and bacteremia and increased the survival rate in a mouse model of bacteremia. Our results demonstrate that FK5P is a safe and promising therapy against Klebsiella species as well as other ESKAPEE pathogens.

Original languageAmerican English
JournalAntimicrobial Agents and Chemotherapy
Volume67
Issue number11
DOIs
StatePublished - Nov 2023

Bibliographical note

Publisher Copyright:
© 2023 American Society for Microbiology. All Rights Reserved.

Keywords

  • Klebsiella oxytoca
  • Klebsiella pneumoniae
  • acute pneumonia
  • bacteremia
  • biofilms
  • ultra-short palmitoylated random peptide mixtures

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