More than 70 different serotypes of Shiga toxin-producing Escherichia coli (STEC) that cause disease in humans have been studied.The symptoms of STEC infection range from mild diarrhea to bloody diarrhea to hemorrhagic colitis (HC) and hemolytic-uremic syndrome (HUS). E. coli O157:H7 (O157) is the STEC strain most often associated with the most severe forms of HC and HUS, which are potentially lethal in children or the elderly.The source of the illnesses is often traced to the consumption of contaminated food, water, or direct animal contact. Using state-of-the-art translational and multi-disciplinary approaches, wehave identified small-molecule inhibitors (SMI) targeting E. colicatabolic pathway enzyme methylthioadenosinenucleosidase (MTN),as an alternative and adjunctive therapeutic intervention to combat drug resistance and biofilm formation in O157. Our discovery is significant and innovative because (1) the new class of SMIs are less likely tocause drug-resistance due to their novel mechanisms of actions in which they inhibit bacterial virulence and growth instead of apply selection pressure to kill. If used alone, non-severe infections treated by these SMIs can be eliminated by host immune systems, potentially leading to reduced antibiotic use and drug-resistance in cattle;(2) the new class of SMIs have complementary anti-bacterial effects to existing antibiotics given to cattle, thus they can be also used as adjunctive therapy to potentiate the activity of existing antibiotics in the cases of severe infections.