Doctor of Philosophy, The Ohio State University, 2021, Comparative and Veterinary Medicine
Avian pathogenic E. coli (APEC), an extra-intestinal pathogenic E. coli (ExPEC), is one of the most common bacterial pathogens affecting poultry, including broilers, layers, breeders, turkeys and many other avian species. It causes high morbidity and mortality (up to 20%), decrease in production and increase in condemnation of carcasses (up to 43%) during slaughter, thus resulting in substantial economic losses to the poultry industry worldwide. Recent reports have suggested APEC as a source of human extra-intestinal infections, including urinary tract infections and sometimes meningitis. Further, APEC is also considered as a source of antibiotic resistance genes (ARGs) to human pathogens. Therefore, APEC is a pathogen of significant importance to both animal and human health. Currently, antibiotics are commonly used to control APEC infections; however, the increasing emergence of resistance to antibiotics and FDA (Food and Drug Administration) restrictions on using antibiotics in food-producing animals necessitate the development of new and effective antibacterials that can circumvent the resistance problem. Antibacterials targeting the outer membrane (OM) of bacteria can evade the problem of resistance in Gram-negative bacteria such as APEC. To this end, we discovered and evaluated small molecule (SM) growth inhibitors (GIs) and antimicrobial peptides (AMPs) affecting OM of APEC. We uncovered their antibacterial targets in the OM of APEC and assessed their impact on gut microbiome. We further demonstrated the potential of GIs as adjuvants to current antibiotics, including one of the last-resort antibiotics, colistin.
A total of 11 GIs (GI1 – GI11) with bactericidal activity against APEC were identified through high throughput screening of pre-selected enriched small molecule library. Eight GIs that were effective and showed low toxicity in vitro in cultured epithelial and macrophage cells, red blood cells, and in vivo in wax moth (Galleria mellonella) larva mode (open full item for complete abstract)
Committee: Gireesh Rajashekara (Advisor); James Fuchs (Committee Member); Vlasova Anastasia (Committee Member); Hale Vanessa (Committee Member)
Subjects: Animal Diseases; Bioinformatics; Microbiology; Molecular Biology; Molecules; Pharmaceuticals; Therapy