Microbial Membrane Modification through Rational Design, Synthesis, and Implementation of Conjugated Oligoelectrolytes

Demarcating the boundary between bacterial cells and the external environment, the membrane provides a selective barrier for the flux of chemical entities into- and out of- the cells. As such, membrane properties have significant implications in a number of technologies. In whole-cell biocatalysis and bioenergy production, for example, the barrier imposed by the membrane limits efficient flow of substrates, products, and electrical current. This barrier is also partly responsible for the difficulties in treating certain infections by preventing antibiotics from reaching their targets within cells. Additionally, the membrane functions to guide the physical interactions of cells with other biotic and abiotic components of their environment. Thus, the selective modulation of membrane properties represents a powerful tool that can benefit numerous microbe-based technologies. Conjugated oligoelectrolytes (COEs) are a class of compounds defined by a π-delocalized backbone consisting of a discrete number of repeat units and pendant ionic functionalities. Specific subsets of COEs possess the proper distribution of charge and hydrophobic/hydrophilic balance to permit spontaneous intercalation into model- and natural- membranes. The consequences of COE intercalation into membranes are variable and highly dependent on molecular structure. In this work, we will probe the structure-activity relationships that govern COE effects on membranes. Additionally, the strategic design and synthesis of COEs to achieve specific effects on membranes will be described. In one study, a homologous series of COEs will be employed to elucidate how structural elements direct antimicrobial and membrane-permeabilizing properties. Through careful examination of independent structural components, an improved understanding of COE structure-property relationships will be developed and applied in subsequent studies. In a separate effort, the design of a COE photo-actuator for on-demand membrane permeabilization will be described and its activity will be demonstrated in model-membrane vesicles as well as living cells. A novel class of asymmetric COEs bearing functional handles will be discussed with an emphasis on design and synthesis. The use of one such compound as an interlayer for improved biotic-abiotic interfaces in bioelectronic applications will be described in detail. Additional representative compounds of this class will be investigated as “membrane-anchors” for the localization of small molecules and proteins to the surface of cells as well as a means to direct cell-surface and cell-cell interactions. Finally, preliminary studies into the potential for COEs to represent a new class of antibiotics will be presented with a focus on structural optimization for improved selectivity toward bacterial cells