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ACS medicinal chemistry letters
Aug 11, 2016;7 (8): 741-5.

Modulation of Backbone Flexibility for Effective Dissociation of Antibacterial and Hemolytic Activity in Cyclic Peptides.

Alberto Oddo, Thomas T Thomsen, Hannah M Britt, Anders Løbner-Olesen, Peter W Thulstrup, John M Sanderson, Paul R Hansen
Author Information
  1. Alberto Oddo: Department of Drug Design and Pharmacology, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark; Department of Chemistry, Durham University, South Road, DH1 3LE Durham, United Kingdom.
  2. Thomas T Thomsen: Department of Biology, University of Copenhagen , Ole Maaløes Vej 5, 2200 Copenhagen, Denmark.
  3. Hannah M Britt: Department of Chemistry, Durham University , South Road, DH1 3LE Durham, United Kingdom.
  4. Anders Løbner-Olesen: Department of Biology, University of Copenhagen , Ole Maaløes Vej 5, 2200 Copenhagen, Denmark.
  5. Peter W Thulstrup: Department of Chemistry, University of Copenhagen , Universitetsparken 5, 2100 Copenhagen, Denmark.
  6. John M Sanderson: Department of Chemistry, Durham University , South Road, DH1 3LE Durham, United Kingdom.
  7. Paul R Hansen: Department of Drug Design and Pharmacology, University of Copenhagen , Universitetsparken 2, 2100 Copenhagen, Denmark.
PMID: 27563396 DOI: 10.1021/acsmedchemlett.5b00400

Abstract

Bacterial resistance to antibiotic therapy is on the rise and threatens to evolve into a worldwide emergency: alternative solutions to current therapies are urgently needed. Cationic amphipathic peptides are potent membrane-active agents that hold promise as the next-generation therapy for multidrug-resistant infections. The peptides' behavior upon encountering the bacterial cell wall is crucial, and much effort has been dedicated to the investigation and optimization of this amphipathicity-driven interaction. In this study we examined the interaction of a novel series of nine-membered flexible cyclic AMPs with liposomes mimicking the characteristics of bacterial membranes. Employed techniques included circular dichroism and marker release assays, as well as microbiological experiments. Our analysis was aimed at correlating ring flexibility with their antimicrobial, hemolytic, and membrane activity. By doing so, we obtained useful insights to guide the optimization of cyclic antimicrobial peptides via modulation of their backbone flexibility without loss of activity.

Keywords

Cyclic peptides antimicrobial peptides flexible peptides hemolytic activity membrane activity

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