Designing Simple Lipidated Lysines: Bifurcation Imparts Selective Antibacterial Activity

Abstract

In the global effort to thwart antimicrobial resistance, lipopeptides are an important class of antimicrobial agents, especially against Gram-negative infections. In an attempt to circumvent their synthetic complexities, we designed simple membrane-active agents involving only one amino acid and two lipid tails. Herein we show that the use of two short lipid tails instead of a single long one significantly increases selective antibacterial activity. This study yielded several selective antibacterial compounds, and investigations into the properties of this compound class were conducted with the most active compound. Fluorescence spectroscopic studies revealed the capacity of the representative compound to cause depolarization and permeabilization of bacterial cell membranes. This membrane-active nature of the compound imparts superior activity against persister cells, biofilms, and planktonic cells. Topical application of the compound decreased bacterial burden in mice inflicted with burn-infections caused by Acinetobacter baumannii. We anticipate that the design principles described herein will direct the development of several antimicrobial agents of clinical importance.