Project Grant K99DE032311

DETERMINING THE MECHANISM AND IMPACT OF STREPTOCOCCAL RAS-RIPPS ON THE HUMAN ORAL MICROBIOME - PROJECT SUMMARY THE HUMAN ORAL MICROBIOME IS HOME TO A UNIQUE GROUP OF BACTERIA WITH THE ABILITY TO AFFECT THE OVERALL HEALTH OF THE HUMAN HOST: STREPTOCOCCI SPP. THIS GROUP IS INVOLVED IN A WIDE RANGE OF DISEASES, FROM DENTAL CARIES TO INFECTIVE ENDOCARDITIS. THEY INCLUDE IMPORTANT ORAL PATHOGENS SUCH AS THE CARIOGENIC STREPTOCOCCUS MUTANS AND COMMENSAL ORGANISMS SUCH AS STREPTOCOCCUS MITIS. THESE IMPORTANT ORAL MEMBERS PRODUCE A LARGE ARRAY OF RADICAL-S-ADENOSYLMETHIONINE RIBOSOMALLY SYNTHESIZED AND POST-TRANSLATIONALLY MODIFIED PEPTIDES (RAS-RIPPS). THE NEWLY IDENTIFIED COMPOUNDS INCLUDE A WEALTH OF CHEMICAL STRUCTURES AND HAVE BEEN FOUND TO INHIBIT THE GROWTH OF OTHER ORAL STREPTOCOCCI, AS WELL AS MODULATE THE BEHAVIOR OF PRODUCER ORGANISMS THEMSELVES. THE INITIAL GOAL OF THIS PROPOSAL IS TO ELUCIDATE THE MECHANISM OF ACTION OF THE RAS-RIPP TRYGLYSIN FROM S. MUTANS, AND TO EXAMINE ITS IMPACT ON THE FUNCTIONAL ORAL MICROBIOME. UPON DEFINING TRYGLYSIN'S MECHANISM OF ACTION ON ORAL STREPTOCOCCI AND THE ORAL MICROBIOME, THIS STUDY WILL BE EXPANDED TO EXAMINE THE BIOLOGICAL SIGNIFICANCE OF OTHER RAS-RIPPS PRODUCED BY STREPTOCOCCI: STREPTOSACTIN, SUISACTIN, ROTAPEPTIDES, AND NXXC FAMILY PEPTIDES. WHILE THE CHEMICAL STRUCTURE AND SYNTHESIS OF THESE PEPTIDES HAS BEEN DEFINED, THE BIOLOGICAL SIGNIFICANCE OF THESE IDENTIFIED RAS-RIPPS IS UNEXPLORED. GIVEN THE IMPORTANT STATUS OF STREPTOCOCCI SPP. TO THE HEALTH OF THE HUMAN ORAL MICROBIOTA, THIS REPRESENTS A MAJOR GAP IN KNOWLEDGE ABOUT A CLASS OF PEPTIDES WITH HUGE POTENTIAL IMPACTS ON OVERALL ORAL HEALTH. THIS PROPOSAL AIMS TO CREATE A RESEARCH PLATFORM FOR STUDYING RAS-RIPPS FROM ORAL STREPTOCOCCI, DEFINING THEIR FUNCTION, AND EXAMINING SHIFTS IN THE FUNCTIONAL ORAL MICROBIOME IN RESPONSE TO THEIR PRODUCTION. EXECUTING THIS RESEARCH PROGRAM AT THE UNIVERSITY OF ILLINOIS AT CHICAGO (UIC) WILL ALLOW FOR THE ESTABLISHMENT OF THE CANDIDATE AS AN INDEPENDENT RESEARCHER AND PROVIDE AVENUES FOR THE ACHIEVEMENT OF THE CANDIDATE'S CAREER GOALS: ESTABLISHING A PRODUCTIVE AND FIRST-RATE RESEARCH LABORATORY AND SECURING A TENURED FACULTY POSITION AT A MAJOR RESEARCH INSTITUTION.