Structural Biology Core

PROJECT SUMMARY / ABSTRACT Bacterial antibiotic resistance is a major global health threat. Our proposal aims to develop immunotherapies focused on the surface glycans of bacteria as a potential paradigm shift in the fight against life-threatening bacteria, for which current therapeutic options are limited. We aim to develop novel antibody-based vaccines and antibody therapeutics to help meet the evolving challenge presented by these bacteria. In particular, the grant will focus on developing and characterizing antibodies and MHC class II to four classes of glycans and glycopeptides from the capsular antigens, peptidoglycans, teichoic acids and O-linked glycans from three organisms: Staphylococcus aureus (Sa), Klebsiella pneumoniae (Kp), and Neisseria gonorrhea (Ng). The glycan antigens will be presented to the immune system linked to peptides and conjugated to chemically defined sites on virus-like particles. The Structural Biology Core 3 will utilize high-throughput x-ray crystallography with state-of-the art tools, instrumentation and facilities to structurally and biophysically characterize the elicited antibodies in complex with the glycans used for immunization. In addition, we will examine complexes of MHC Class II molecules with designed glycopeptides to explore how these unique structures are presented to T cells. Our structural results will be used to guide iterative rounds of modifications to the antigens, linkers and peptides with Projects 1-4 and Cores 1,2 to focus and enhance the immune response to these challenging targets. The structures will also guide in the engineering of antibodies to improve their therapeutic potential with Project 4 and Core 2. All studies will be coordinated through the Administrative Core.