TY - JOUR
T1 - A miniature mimic of host defense peptides with systemic antibacterial efficacy
AU - Sarig, Hadar
AU - Livne, Liran
AU - Held-Kuznetsov, Victoria
AU - Zaknoon, Fadia
AU - Ivankin, Andrey
AU - Gidalevitz, David
AU - Mor, Amram
PY - 2010/6
Y1 - 2010/6
N2 - 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.
AB - 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.
KW - Antimicrobial peptide
KW - Chemical mimicry
KW - Drug design
KW - Drug resistance
KW - Mechanism of action
UR - http://www.scopus.com/inward/record.url?scp=77953509929&partnerID=8YFLogxK
U2 - 10.1096/fj.09-149427
DO - 10.1096/fj.09-149427
M3 - 文章
C2 - 20124435
AN - SCOPUS:77953509929
VL - 24
SP - 1904
EP - 1913
JO - FASEB Journal
JF - FASEB Journal
SN - 0892-6638
IS - 6
ER -