title: A miniature mimic of host defense peptides with systemic antibacterial efficacy.
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 C(12(omega7))K-beta(12)) 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 C(12(omega7))K-beta(12) 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.
authors.affiliation: Department of Biotechnology and Food Engineering, Technion-Israel Institute of Technology, Haifa, Israel.
authors.forename: Hadar
authors.initials: H
authors.lastname: Sarig
authors.forename: Liran
authors.initials: L
authors.lastname: Livne
authors.forename: Victoria
authors.initials: V
authors.lastname: Held-Kuznetsov
authors.forename: Fadia
authors.initials: F
authors.lastname: Zaknoon
authors.forename: Andrey
authors.initials: A
authors.lastname: Ivankin
authors.forename: David
authors.initials: D
authors.lastname: Gidalevitz
authors.forename: Amram
authors.initials: A
authors.lastname: Mor
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D023181:Antimicrobial Cationic Peptides / Q000494:pharmacology*; D001419:Bacteria / Q000187:drug effects*; D001424:Bacterial Infections / Q000188:drug therapy*; D032701:Biomimetics; D005347:Fibroblasts / Q000378:metabolism; D008239:Lysine / Q000737:chemistry; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D008826:Microbial Sensitivity Tests; D020349:Surface Plasmon Resonance; D014961:X-Ray Diffraction
chemical_list: D000900:Anti-Bacterial Agents; D023181:Antimicrobial Cationic Peptides; D008239:Lysine