Stapling of Peptides Potentiates: The Antibiotic Treatment of Acinetobacter baumannii In Vivo

Gina K. Schouten, Felix M. Paulussen, Oscar P. Kuipers, Wilbert Bitter, Tom N. Grossmann*, Peter van Ulsen

*Corresponding author for this work

Research output: Contribution to JournalArticleAcademicpeer-review

Abstract

The rising incidence of multidrug resistance in Gram-negative bacteria underlines the urgency for novel treatment options. One promising new approach is the synergistic combination of antibiotics with antimicrobial peptides. However, the use of such peptides is not straightforward; they are often sensitive to proteolytic degradation, which greatly limits their clinical potential. One approach to increase stability is to apply a hydrocarbon staple to the antimicrobial peptide, thereby fixing them in an α-helical conformation, which renders them less exposed to proteolytic activity. In this work we applied several different hydrocarbon staples to two previously described peptides shown to act on the outer membrane, L6 and L8, and tested their activity in a zebrafish embryo infection model using a clinical isolate of Acinetobacter baumannii as a pathogen. We show that the introduction of such a hydrocarbon staple to the peptide L8 improves its in vivo potentiating activity on antibiotic treatment, without increasing its in vivo antimicrobial activity, toxicity or hemolytic activity.

Original languageEnglish
Article number273
Pages (from-to)1-16
Number of pages16
JournalAntibiotics
Volume11
Issue number2
Early online date19 Feb 2022
DOIs
Publication statusPublished - Feb 2022

Bibliographical note

Funding Information:
Funding: This project has received funding from the European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant, agreement no. 713669. Furthermore, this project, with the project number 16433, is part of the research program NACTAR, which is partly financed by the Dutch Research Counsel (NOW).

Publisher Copyright:
© 2022 by the authors. Licensee MDPI, Basel, Switzerland.

Keywords

  • Stapled antimicrobial peptides
  • Synergy
  • Zebrafish larvae infection model

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