SUBTHERAPEUTIC USE OF ANTIBIOTICS FOR GROWTH PROMOTION AND DISEASE PREVENTION HAS BEEN PHASED OUT IN THE U.S. LIVESTOCK INDUSTRY BY THE FDA AS OF JANUARY 2017. ALTHOUGH VARIOUS ALTERNATIVES TO ANTIBIOTICS HAVE BEEN EXPLORED, NONE IS ABLE TO MATCH THE EFFICACY OF ANTIBIOTICS. THROUGH HIGH THROUGHPUT SCREENING OF OVER 5,000 SMALL-MOLECULE COMPOUNDS, WE RECENTLY DISCOVERED SEVERAL CLASSES OF EPIGENETIC COMPOUNDS THAT SYNERGIZE WITH EACH OTHER IN ENHANCING THE SYNTHESIS OF HOST DEFENSE PEPTIDES (HDPS), A CRITICAL COMPONENT OF ANIMAL INNATE IMMUNITY. THESE DISCOVERIES PROVIDED A TIMELY OPPORTUNITY TO INVESTIGATE THE POTENTIAL OF THESE EPIGENETIC COMPOUNDS AS NOVEL ANTIBIOTIC ALTERNATIVES. THE LONG-TERM GOAL OF OUR RESEARCH IS TO DEVELOP HDP-INDUCING COMPOUNDS AS NEXT-GENERATION ANTIBIOTIC ALTERNATIVES FOR LIVESTOCK USE. THE OVERALL GOAL OF THIS GRANT IS TO EVALUATE THE EFFICACY OF NEWLY-IDENTIFIED EPIGENETIC COMPOUNDS IN HDP INDUCTION AND BACTERIAL CLEARANCE IN A CHICKEN MODEL OF NECROTICENTERITIS. THE CENTRAL HYPOTHESIS IS THAT STRATEGIES TO ENHANCE HDP SYNTHESIS WILL PROMOTE BACTERIAL CLEARANCE. TWO SPECIFIC OBJECTIVES ARE PROPOSED TO 1) IDENTIFY THE MOST EFFICACIOUS EPIGENETIC COMPOUNDS AND THEIR COMBINATIONS TO INDUCE HDP SYNTHESIS WITHOUT TRIGGERING INFLAMMATION, AND 2) DEMONSTRATE SELECTED EPIGENETIC COMPOUNDS TO BE AS EFFICIENT AS IN-FEED ANTIBIOTICS IN PROMOTING GUT HEALTH AND PATHOGEN CLEARANCE. THE OUTCOME OF THIS PROJECT WILL PAVE THE WAY FOR THE DEVELOPMENT OF AN URGENTLY NEEDED, HUGELY PROMISING, AND PARADIGM-SHIFTING ANTIBIOTIC ALTERNATIVE TECHNOLOGY THAT MEETS THE FDA MANDATES AS WELL AS PUBLIC DEMANDS FOR SAFE, HEALTHY, AND ECOLOGICALLY RESPONSIBLE ANIMAL PRODUCTS.