Glycopolymers as Cellular Glues

PROJECT SUMMARY/ABSTRACT Antibiotics have improved our ability to treat infections, but antibiotic resistance is now an urgent public health crisis, with global deaths from bacterial infections now exceeding 2 million annually. This rise in resistance demands innovative strategies to combat pathogens effectively. As an alternative to pursuing small-molecule antibiotics, I propose harnessing the body’s own immune mechanisms to combat pathogens effectively. I plan to promote interactions between bacteria and human glycan-binding proteins on immune cells for new antimicrobial therapies. This proposal aims to create “cellular glues” — molecules designed to enhance the interactions between immune cells and pathogenic bacteria, ensuring the effective destruction of the pathogens. I will develop glycopolymers that bind to glycan-binding proteins on the surface of the target pathogen, Pseudomonas aeruginosa (PsA), and glycan-binding receptors on immune cells, specifically antigen-presenting cells. I will assess the ability of glycopolymers to mediate 1) bacteria recognition, activation, and signaling by dendritic cells, critical informers of T cell response and instructors of adaptive immunity, 2) bacteria killing by macrophages, key phagocytic cells that also process and present antigens, and 3) improved innate and adaptive immune responses in vivo. I envision this approach will provide insight into how glycan recognition by human lectins influences immune responses to pathogens. Moreover, this versatile strategy could be expanded to tackle other multidrug-resistant bacteria like Enterococcus faecium and Klebsiella pneumoniae, as these pathogens share carbohydrate-binding proteins that are targetable by this design. A successful demonstration of the utility of this approach would lay the groundwork for directing immune responses against growing threats like fungi or even tumor cells.