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 C12K-3 beta(10), with broad-spectrum activity (MIC90 = 6.2 mu M) and low hemotoxicity (LC50 > 100 mu M). Whereas C12K-3 beta(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).