Project Grant R15GM152996

DEVELOPMENT OF BIOINSPIRED TANDEM SEMICONDUCTOR/PEROXIDASE SYSTEMS FOR MICROBIOCIDAL APPLICATIONS. - ABSTRACT MICROBIAL BIOFILMS ARE A SIGNIFICANT SOURCE OF MICROBIAL INFECTIONS AND REPRESENT AN ONGOING BURDEN TO THE HEALTHCARE INDUSTRY. RECENT STUDIES INDICATE THAT AN ESTIMATED 65% - 80% OF ALL BACTERIAL INFECTIONS DERIVE FROM BIOFILM FORMATION. IN THE CASE OF TOPICAL INFECTIONS, BIOFILM FORMATION IS ASSOCIATED WITH WOUND CHRONICITY. INDEED, IT HAS BEEN REPORTED THAT MICROBIAL BIOFILM IS PRESENT IN OVER 90% OF WOUNDS THAT ARE CHRONIC IN NATURE OR ARE OTHERWISE SLOW TO HEAL. THESE CHRONIC WOUNDS AFFECT AN ESTIMATED 2% OF THE TOTAL POPULATION OF THE UNITED STATES, ANNUALLY. THE GLOBAL ANNUAL COST FOR MEDICAL CARE ASSOCIATED WITH CHRONIC WOUNDS IS PREDICTED TO REACH $3.5 BILLION THIS YEAR. TAKEN IN TOTAL, IT IS CLEAR THAT THERE IS AN URGENT NEED TO DEVELOP NEW STRATEGIES TO BOTH PREVENT NEW BIOFILM FORMATION AS WELL AS COMBAT ESTABLISHED BIOFILMS. THE METAL-FREE SEMICONDUCTOR GRAPHITIC CARBON NITRIDE (G-C3N4) IS AN ATTRACTIVE TARGET FOR THE DEVELOPMENT OF SUCH TECHNOLOGIES DUE TO ITS' ESTABLISHED ABILITY TO EFFICIENTLY REDUCE ELEMENTAL OXYGEN TO GENERATE A VARIETY OF REACTIVE OXYGEN SPECIES (ROS), INCLUDING THE SUPEROXIDE RADICAL ANION (O2-) AND HYDROGEN PEROXIDE (H2O2). THIS ACTIVITY EFFECTIVELY MIMICS THE OXIDATIVE BURST EXHIBITED BY NEUTROPHILS AS PART OF THE MAMMALIAN IMMUNE RESPONSE TO INVASIVE ORGANISMS. NOTABLY, THE ANTIMICROBIAL ACTIVITY OF ROS, INCLUDING H2O2, CAN BE ENHANCED SEVERAL ORDERS OF MAGNITUDE VIA CONVERSION INTO A VARIETY OF REACTIVE HALOGEN SPECIES (RHS), INCLUDING HOCL, HOI AND OTHERS. THE REACTIVE NATURE OF ROS/RHS MAY ALSO IMPACT A VARIETY OF POPULATION-DEPENDENT EVENTS BY INTERRUPTING MICROBIAL QUORUM SIGNALING PROCESSES. TAKING INSPIRATION FROM THIS ACTIVITY, WE HYPOTHESIZE THAT TANDEM G-C3N4/PEROXIDASE SYSTEMS, WHICH DIRECTLY COUPLE THE EFFICIENT PHOTOCHEMICAL ROS FORMATION OF THE SEMICONDUCTOR WITH A SECONDARY HALOGENATION STEP, WILL EXHIBIT ENHANCED UTILITY FOR ANTIMICROBIAL, ANTI-BIOFILM AND ANTI-QUORUM SENSING APPLICATIONS. TO FACILITATE THE SUCCESSFUL DEVELOPMENT OF THESE NEW MICROBIOCIDAL AGENTS, EXPERIMENTS INCLUDED AS PART OF SPECIFIC AIM 1 WILL BE DIRECTED TOWARD THE SYNTHESIS AND CHARACTERIZATION OF A SERIES OF TANDEM G-C3N4/PEROXIDASE SYSTEMS THAT DEMONSTRATE EFFICIENT FORMATION OF ROS AND RHS. SUCCESSFUL PRODUCTION OF THE DESIRED RHS WILL BE CONFIRMED BY A COMBINATION OF SPECTROPHOTOMETRIC ASSAYS AND MOLECULAR TRAPPING EXPERIMENTS. EXPERIMENTS IN AIM 2 WILL SERVE TO VALIDATE THE UTILITY OF THE TANDEM G-C3N4/PEROXIDASE SYSTEMS FOR MICROBIOCIDAL, ANTI-BIOFILM AND ANTI-QUORUM SENSING APPLICATIONS. COMPLEMENTARY MECHANISTIC AND MAMMALIAN CELL TOXICITY STUDIES WILL PROVIDE CRITICAL INFORMATION ABOUT THE RELATIVE UTILITY OF THE BROADER CLASS OF ORGANIC SEMICONDUCTORS, INCLUDING G- C3N4, FOR BIOMEDICAL AND ANTIMICROBIAL APPLICATIONS. ALL OF THE EXPERIMENTS DESCRIBED IN THIS PROPOSAL WILL DIRECTLY INCORPORATE UNDERGRADUATE STUDENT RESEARCHERS, WHO HAVE BEEN RESPONSIBLE FOR GENERATING MUCH OF THE PRELIMINARY DATA THAT IS PRESENTED HERE. TAKEN IN TOTAL, THE EXPERIMENTS THAT ARE INCORPORATED INTO THIS PROPOSAL WILL SERVE TO ESTABLISH THE BIOMEDICAL UTILITY OF G-C3N4-BASED MATERIALS AND OTHER, RELATED ORGANIC SEMICONDUCTORS AS NOVEL FUNCTIONAL DEVICES CAPABLE OF COMBATTING MICROBIAL BIOFILMS AND CHRONIC INFECTIONS.