Intracellular Processing of Cell-penetrating Oligothioetheramides

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Bacteria can develop resistance to antibiotics at alarming rates. This poses a significant threat to public health and national security. This threat is even worse with the increasing number of pathogens that can enter and colonize cells. Polymers can be useful in helping antibiotics enter these cells and attack the pathogens. This project will explore the mechanisms and rates of such antibiotic delivery. New concepts and models pertaining to these systems will be developed. Undergraduate and graduate students will be engaged in executing this project. High school students engaged in a 4-H Focus for Teens workshop will be trained to present a polymer science experimental module to their local 4-H clubs. These activities will stimulate the development of a highly productive and inclusive STEM workforce. Cell penetrating oligothioetheramides are a new class of non-charged, cell-penetrating macromolecules that rapidly enter cells across different cell lines in a highly diffuse pattern. This project will expand the understanding of how these macromolecular agents are processed within the cell by developing a kinetic model that directly measures intracellular bond cleavage. The intracellular degradation rate constant will be specific for each antibiotic prodrug and cell line. This information will be used to investigate how linker composition and antibiotic type influence the kinetics of intracellular antibiotic release and thus antibacterial activity. The database of kinetic parameters obtained will inform the decision process leading up to the choice of a cleavable bond for a particular polymer-drug conjugate. Furthermore, the kinetic parameters will also be of significant value to the scientists and engineers working on compartmental and physiological models for a variety of applications.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.