Molecular design of antimicrobial conjugated oligoelectrolytes with enhanced selectivity toward bacterial cells

Abstract

A series of cationic conjugated oligoelectrolytes (COEs) was designed to understand how variations in molecular dimensions impact the relative activity against bacteria and mammalian cells. These COEs kept a consistent distyrylbenzene framework but differed in the length of linker between the core and the cationic site and the length of substitute on the quaternary ammonium functioned group. Their antimicrobial efficacy, mammalian cell cytotoxicity, hemolytic activity, and cell association were determined. We find that hydrophobicity is a factor that controls the degree of COE association to cells, but <i>in vitro</i> efficacy and cytotoxicity depend on more subtle structural features. <b>COE2-3C-C4butyl</b> was found to be the optimal structure with a minimum inhibitory concentration (MIC) of 4 μg mL^-1 against <i>E. coli</i> K12, low cytotoxicity against HepG2 cells and negligible hemolysis of red blood cells, even at 1024 μg mL^-1. A time-kill kinetics study of <b>COE2-3C-C4butyl</b> against <i>E. coli</i> K12 demonstrates bactericidal activity. These findings provide the first systematic investigation of how COEs may be modulated to achieve low mammalian cell cytotoxicity with the long-range perspective of finding candidates suitable for developing a broad-spectrum antimicrobial agent.