Rational Design and Synthesis of Membrane-active Conjugated Oligoelectrolytes for Biological Applications

Lipid bilayers are omnipresent in biological systems as a barrier protecting intracellular components from the external environment. The semi-permeable behavior of membranes selectively controls flux of chemicals into and out of the cells maintaining chemical balances. This behavior is also a main obstacle for delivering or harvesting chemicals into and from cells. Modifying membrane properties to enhance chemical transport therefore has implications for many cell-based applications.Conjugated oligoelectrolytes (COEs) are a class of synthetic compounds that contain a π-conjugated backbone with aliphatic linkers bearing ionic functionalities. Given appropriate molecular dimensions and hydrophobic/hydrophilic balance that resemble lipid bilayers, a subset of COEs possess an ability to spontaneously intercalate into membranes and subsequently modify membrane properties. In this work, rational design and structure-property relationships of COEs and their ability to permeabilize and disrupt membranes will be presented.In the first work, as an effort to improve membrane permeabilization for whole- cell biocatalysis, a COE containing a non-planar conjugated core will be presented and its impact on lipid bilayers will be discussed. Escherichia coli and Saccharomyces cerevisiae (yeast) will be used as model organisms to show an ability of COEs to accelerate whole-cell biocatalysis rates with reduced toxicity to microorganisms.In a separate study, a homologous series of distyrylbenzene-based COEs will be presented to elucidate the relationship between their structures and their antimicrobial activities and mammalian cell cytotoxicity. The criteria required to achieve high antibacterial selectivity will be discussed. A subsequent study will investigate the impact of hydrogen bonds—another intermolecular force apart from electrostatic and hydrophobic interactions that can be important in lipid interactions—on antimicrobial activities of the COEs. Activities on periplasmic and cytoplasmic membranes of Escherichia coli will be discussed. Additionally, another series of COEs containing amidine moieties will be presented along with preliminary data of their antimicrobial activities against a broad panel of pathogenic bacteria with a focus on Pseudomonas aeruginosa—a clinically relevant pathogen associated with difficult-to-treat infections and with a high propensity for developing antibiotic resistance. Finally, additional results towards developing COEs as a novel class of antibiotics and a method to estimate the “hydrophobicity” of COEs will be discussed