Design and characterization of a broad -spectrum bactericidal acyl-lysyl oligomer.
Previously characterized chemical mimics of host defense peptides belonging to the oligo-acyl-lysyl (OAK) family have so far failed to demonstrate broad-spectrum antibacterial potency combined with selectivity toward host cells. Here, we investigated OAK sequences and characterized a promising representative, designated C(12)K-3beta(10), with broad-spectrum activity (MIC(90) = 6.2 microM) and low hemotoxicity (LC(50) > 100 microM). Whereas C(12)K-3beta(10) exerted an essentially bactericidal effect, E. coli bacteria were killed faster than S. aureus (minutes versus hours). Mechanistic studies addressing this difference revealed that unlike E. coli, S. aureus bacteria undergo a transient rapid bactericidal stage that over time converts to a bacteriostatic effect. This behavior was dictated by interactions with cell wall-specific components. Preliminary efficacy studies in mice using the thigh infection model demonstrated the OAK's ability to significantly affect bacterial viability upon single-dose systemic treatment (2 mg/kg).
Livne
Liran
L
Department of Biotechnology and Food Engineering, Technion-Israel Institute of Technology, Haifa 32000, Israel.
Kovachi
Tchelet
T
Sarig
Hadar
H
Epand
Raquel F
RF
Zaknoon
Fadia
F
Epand
Richard M
RM
Mor
Amram
A
D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology*; D001419:Bacteria / Q000187:drug effects*; D002151:Calorimetry; D002473:Cell Wall / Q000187:drug effects; D004195:Disease Models, Animal; D015195:Drug Design; D007700:Kinetics; D008239:Lysine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D008826:Microbial Sensitivity Tests; D013329:Structure-Activity Relationship; D020349:Surface Plasmon Resonance
D000900:Anti-Bacterial Agents; D008239:Lysine