Amide Moieties Modulate the Antimicrobial Activities of Conjugated Oligoelectrolytes against Gram-negative Bacteria

Cationic conjugated oligoelectrolytes (COEs) are a class of compounds that can be tailored to achieve relevant in vitro antimicrobial properties with relatively low cytotoxicity against mammalian cells. Three distyrylbenzene-based COEs were designed containing amide functional groups on the side chains. Their properties were compared to two representative COEs with only quaternary ammonium groups. The optimal compound, COE2−3C−C3-Apropyl , has an antimicrobial efficacy against Escherichia coli with an MIC=2 μg mL⁻¹, even in the presence of human serum albumin low cytotoxicity (IC₅₀=740 μg mL⁻¹) and minimal hemolytic activity. Moreover, we find that amide groups increase interactions between COEs and a bacterial lipid mimic based on calcein leakage assay and allow COEs to readily permeabilize the cytoplasmic membrane of E. coli. These findings suggest that hydrogen bond forming moieties can be further applied in the molecular design of antimicrobial COEs to further improve their selectivity towards bacteria.     

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

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 in vitro efficacy and cytotoxicity depend on more subtle structural features. COE2-3C-C4butyl was found to be the optimal structure with a minimum inhibitory concentration (MIC) of 4 μg mL⁻¹ against E. coli 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 COE2-3C-C4butyl against E. coli 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.

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.     

Photoswitchable Conjugated Oligoelectrolytes for a Light-Induced Change of Membrane Morphology

The synthesis of a new conjugated oligoelectrolyte (COE), namely DSAzB, is described, which contains a conjugated core bearing a diazene moiety in the center of its electronically delocalized structure. Similar to structurally related phenylenevinylene-based COEs, DSAzB readily intercalates into model and natural lipid bilayer membranes. Photoinduced isomerization transforms the linear trans COE into a bent or C-shape form. It is thereby possible to introduce DSAzB into the bilayer of a cell and disrupt its integrity by irradiation with light. This leads to controlled permeabilization of membranes, as demonstrated by the release of calcein from DMPG/DMPC vesicles and by propidium iodide influx experiments on S. epidermidis. Both experiments support that the permeabilization is selective for the light stimulus, highly efficient, and repeatable. Target-selective and photoinduced actions demonstrated by DSAzB may have broad applications in biocatalysis and related biotechnologies.