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Analogous oligo-acyl-lysines with distinct antibacterial mechanisms

Shahar Rotem^*,1, Inna S. Radzishevsky^*,1, Dmitry Bourdetsky^*, Shiri Navon-Venezia, Yehuda Carmeli and Amram Mor^*,2

^* Department of Biotechnology and Food Engineering. Technion-Israel Institute of Technology; and

Division of Epidemiology, Tel Aviv Sourasky Medical Center, Israel

²Correspondence: Laboratory of Antimicrobial Peptides Investigation (LAPI), Department of Biotechnology and Food Engineering, Technion—Israel Institute of Technology, Haifa, Israel. E-mail: amor{at}tx.technion.ac.il

Bactericidal properties were recently shown to emerge from hydrophobicity and charge buildup in oligo-acyl-lysine (OAK) peptide mimetics. Toward understanding the attributes that govern the activity of this novel antimicrobial system, we compared the functional and mechanistic properties of a known octamer and a newly generated hexamer analog. The data provide strong evidence for multiple similarities that included high tissue stability, low hemolysis, large-spectrum antibacterial activity in vitro, and the ability to prevent Escherichia coli-induced mortality in vivo. Despite these similarities, however, the octamer mode of action involved membrane disruption, unlike the hexamer, which acted predominantly through inhibition of DNA functions with characteristically slower bactericidal kinetics. Collectively, the data support the view that the analogous OAKs induced bacterial death by distinct mechanisms and further suggest that relatively minor differences in the sequence of host defense peptides are responsible for selecting one mechanism over another, possibly in conjunction with differential binding affinities to the external and/or cytoplasmic membrane.—Rotem, S., Radzishevsky, I. S., Bourdetsky, D., Navon-Venezia, S., Carmeli, Y., Mor, A. Analogous oligo-acyl-lysines with distinct antibacterial mechanisms.

Key Words: host defense peptides • peptidomimetics • mechanism of action • intracellular targets

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