STRUCTURE-GUIDED DEVELOPMENT OF INHIBITORS TARGETING GLYCOCONJUGATE BIOSYNTHESIS IN CANCER-ASSOCIATED FUSOBACTERIUM NUCLEATUM - ABSTRACT BACTERIAL GLYCOCONJUGATES ARE CENTRAL MEDIATORS OF HOST-MICROBE INTERACTIONS, INFLUENCING PATHOGENIC AND SYMBIOTIC PROCESSES. IN CANCER ASSOCIATED MICROBES SUCH AS FUSOBACTERIUM NUCLEATUM (F. NUC), GLYCOCONJUGATES LIKE THE LIPOPOLYSACCHARIDES (LPS) AND THE VARIABLE O-ANTIGEN COMPONENT OF THE LPS HAVE BEEN DEMONSTRATED TO PLAY ROLES IN TUMOR PROGRESSION AND THE SUPPRESSION OF IMMUNE RESPONSE AT THE TUMOR SITE. BIOSYNTHESIS OF MANY KEY GLYCOCONJUGATES INCLUDING THE F. NUC O-ANTIGEN IS INITIATED BY PHOSPHOGLYCOSYL TRANSFERASES (PGTS), WHICH TRANSFER GLYCANS FROM UDP-SUGAR DONORS ONTO LIPID CARRIERS. INHIBITING PGTS REPRESENTS A METHOD FOR TARGETED STUDY OF THE ROLE OF GLYCOCONJUGATES LIKE THE O-ANTIGEN, AS WELL AS A METHOD FOR TARGETED ANTIMICROBIAL DEVELOPMENT. THIS REQUIRES AN IMPROVED UNDERSTANDING OF PGT SUBSTRATE BINDING TO GUIDE INHIBITOR DEVELOPMENT. PROGRESS HAS BEEN MADE IN THIS AREA THROUGH THE SOLVING STRUCTURES OF PGTS RELATED TO THE F. NUC O-ANTIGEN PGT, AND IDENTIFICATION OF SUBSTRATE BINDING MOTIFS, BUT ADDITIONAL STUDIES ARE NEEDED TO DEFINE THE DETERMINANTS OF SUGAR SPECIFICITY IN PGT BINDING. THIS PROJECT WILL BUILD ON AND EXPAND EXISTING WORK TO IDENTIFY SPECIFICITY DETERMINANTS IN F. NUC PGTS TO DESIGN TARGETED INHIBITORS. THESE INHIBITORS WILL BE USED TO ASSAY THE ROLE OF THE O-ANTIGEN IN F. NUC DRIVEN TUMOR PROGRESSION, AND WILL ESTABLISH METHODS TO DEVELOP INHIBITORS OF OTHER PGTS WITH THE POTENTIAL TO SERVE AS ANTIMICROBIALS GIVEN THE ESSENTIAL ROLE OF PGT SYNTHESIZED GLYCOCONJUGATES