INTELLECTUAL MERIT: The goal of the proposed research is to gain a fundamental understanding of the intermolecular interactions between a novel class of synthetic phenylene ethynylene (PPE)-based conjugated polyelectrolyte polymers (CPEs) and oligomers (OPEs) with various cellular assemblies that give rise to a remarkably broad spectrum of biocidal activity. The design of this versatile class of compounds is partly inspired by the naturally occurring antimicrobial peptides (AMPs), but with the added advantages of manufacturability, chemical and physical stability, and materials applications. Building on our previous work in characterizing the biocidal activity of the CPEs and OPEs, the project focuses on elucidating the mechanism of toxicity with the ultimate goal of guiding the rational design of novel compounds with optimal toxicity and selectivity. The CPEs and OPEs are cationic and amphiphilic in nature, which provides them the ability to interact with and disrupt the structures, and thereby functions, of multiple cellular targets. Specifically, the PIs plan to evaluate the propensity of CPEs and OPEs with varying chain length, side and end groups, charge density and distribution, and structures to interact with and disrupt the structures of three major types of biological macromolecular assemblies: lipid membranes (Objective 1), proteins and protein assemblies (Objective 2), and nucleic acids (Objective 3). To accomplish this goal, the multidisciplinary team proposes to use a suite of biophysical and materials characterization methods to study the interactions between CPEs and OPEs and their cellular targets. These studies, aimed at connecting the molecular structure with the macroscopic properties, will employ simulations and molecular modeling to gain further insights into the mechanism and nature of the interaction of CPEs and OPEs with cellular substrates at a basic molecular level. Comparing these findings with biocidal activities will enable the PIs to elucidate the toxicity mechanism and structure-function relationship of this novel class of synthetic biomimetic materials.
BROADER IMPACTS: The proposed research will elucidate the molecular mechanism of a class of bioinspired synthetic antimicrobial compounds that holds the potential to combat the global threat of antibiotic resistance. Elucidation of the molecular interactions of amphiphilic macromolecules with biological materials represents a fundamental scientific challenge that has the potential to impact a number of other fields. These include naturally occurring AMPs, natural and synthetic cell penetrating peptides with applications in targeted drug delivery and gene therapy, and amyloid-forming proteins that are implicated in the pathogenesis of neurodegenerative diseases. The proposed research provides a multidisciplinary environment in which graduate and undergraduate students will be trained in modern methodologies required to address important problems at the interfaces between chemistry, physics, engineering, and biology. The PIs are committed to furthering their contributions to expanding the educational mission of the University of New Mexico (UNM) by establishing new Biomedical Engineering degree programs and by taking leadership roles in the Nanoscience and Microsystems Engineering graduate program. They will continue to coordinate and participate in existing outreach efforts at UNM that encourage the participation of under-represented groups, and to expand these existing programs in new directions. Existing outreach programs that the PIs actively engage in include: NSF-Partnership in Research and Education in Materials (PREM), NSMS outreach program, Research Experience for Undergraduates, and the Southwest Center for Microsystems Education. These programs allow the PIs to train and educate K-12, undergraduate and graduate students, and teachers in multidisciplinary methods of science and engineering. Finally, the PIs will also expand the "Bioengineer for a Day" outreach activity to a rural Native American elementary school to interest students in science and engineering at an early age.
