**AWARDS ISSUED PRIOR TO JANUARY 20, 2025, WERE FUNDED UNDER PREVIOUS ADMINISTRATIONS AND MAY NOT REFLECT THE PRIORITIES AND POLICIES OF THE CURRENT ADMINISTRATION.** THE AVIAN PATHOGENIC E. COLI (APEC) IS ONE OF THE MAJOR BACTERIAL PATHOGENS OF SIGNIFICANT CONCERNS TO THE US AND GLOBAL POULTRY INDUSTRY. APEC CAUSES WIDE RANGE OF LOCALIZED AND SYSTEMIC INFECTIONS IN POULTRY INCLUDING YOLK SAC INFECTION OMPHALITIS RESPIRATORY TRACT INFECTION SWOLLEN HEAD SYNDROME SEPTICEMIA POLYSEROSITIS COLIGRANULOMA ENTERITIS CELLULITIS AND SALPHINGITIS; COLLECTIVELY REFERRED AS COLIBACILLOSIS. COLIBACILLOSIS CULMINATES IN MULTI-MILLION DOLLARS ANNUAL LOSSES TO ALL THE FACETS OF POULTRY INDUSTRY AND REMAINS AS A SERIOUS IMPEDIMENT TO THE SUSTAINABLE POULTRY PRODUCTION WORLDWIDE. CURRENT CONTROL METHODS USING ANTIBIOTIC MEDICATION AND VACCINATION HAVE LIMITATION AS APEC IS RESISTANCE TO MULTIPLE ANTIBIOTICS AND THE AVAILABLE VACCINES FAIL TO CONFER PROTECTION AGAINST DIVERSE AND HETEROLOGOUS APEC SEROTYPES. THEREFORE DEVELOPING NEW AND POTENT ANTI-APEC THERAPEUTICS AS AN ALTERNATIVE TO CURRENT CONTROL MEASURES ARE URGENTLY NEEDED. WE PREVIOUSLY IDENTIFIED PROBIOTIC-DERIVED ANTIMICROBIAL PEPTIDES (P-1 AND P-2) THAT IN SMALL PILOT STUDIES REDUCED THE COLONIZATION OF APEC IN CECUM AND INTERNAL ORGANS OF CHICKENS. THESE PEPTIDES ARE HEAT AND PROTEOLYSIS RESISTANT EFFECTIVE AGAINST DIVERSE APEC SEROTYPES ANTIBIOTIC-RESISTANT APEC STRAINS AND AGAINST BIOFILM-PROTECTED APEC. FURTHER THESE PEPTIDES FUNCTION BY DISRUPTING OUTER MEMBRANE OF APEC A MECHANISM TO WHICH RESISTANCE IS LESS LIKELY TO OCCUR. HERE WE PLAN TO EVALUATE THE EFFICACY SAFETY AND APPLICABILITY OF IDENTIFIED ANTI-APEC PEPTIDES (P-1 AND P-2) IN DRINKING WATER OF CHICKENS AND TO ELUCIDATE THEIR MECHANISM(S) OF ACTION. OUR OVERARCHING GOAL IS TO DEVELOP THESE PEPTIDES AS NEW ANTI-APEC THERAPEUTICS AS AN ALTERNATIVE TO ANTIBIOTICS. WE EXPECT THAT THESE PEPTIDES WILL PROVIDE A NOVEL THERAPEUTIC SOLUTION TO ENHANCE THE CONTROL OF APEC INFECTIONS IN POULTRY WHICH WILL CONSEQUENTLY PROMOTE THE SUSTAINABLE POULTRY PRODUCTION AND BENEFIT THE PUBLIC HEALTH.