A miniature mimic of host defense peptides with systemic antibacterial efficacy

Hadar Sarig, Liran Livne, Victoria Held-Kuznetsov, Fadia Zaknoon, Andrey Ivankin, David Gidalevitz, Amram Mor*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

35 Scopus citations

Abstract

Oligomers of acylated lysines (OAKs) are synthetic mimics of host defense peptides (HDPs) with promising antimicrobial properties. Here we challenged the OAK concept for its ability to generate both systemically efficient and economically viable lead compounds for fighting multidrug-resistant bacteria. We describe the design and characterization of a miniature OAK composed of only 3 lysyls and 2 acyls (designated C12(ω7)K-β12) that preferentially targets gram-positive species by a bacteriostatic mode of action. To gain insight into the mechanism of action, we examined the interaction of OAK with various potential targets, including phospholipid bilayers, using surface plasmon resonance, and Langmuir monolayers, using insertion assays, epifluorescence microscopy, and grazing incidence X-ray diffraction, in a complementary manner. Collectively, the data support the notion that C12(ω7)K-β12 damages the plasma-membrane architecture similarly to HDPs, that is, following a near-classic 2-step interaction including high-affinity electrostatic adhesion and a subsequent shallow insertion that was limited to the phospholipid head group region. Notably, preliminary acute toxicity and efficacy studies performed with mouse models of infection have consolidated the potential of OAK for treating bacterial infections, including systemic treatments of methicillin-resistant Staphylococcus aureus. Such simple yet robust chemicals might be useful for various antibacterial applications while circumventing potential adverse effects associated with cytolytic compounds.

Original languageEnglish
Pages (from-to)1904-1913
Number of pages10
JournalFASEB Journal
Volume24
Issue number6
DOIs
StatePublished - Jun 2010
Externally publishedYes

Keywords

  • Antimicrobial peptide
  • Chemical mimicry
  • Drug design
  • Drug resistance
  • Mechanism of action

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