| Summary: | Non-typhoidal <i>Salmonella</i> ingeniously scavenges energy for growth from tyramine (TYR) and d-glucuronic acid (DGA), both of which occur in the host as the metabolic byproducts of the gut microbial metabolism. A critical first step in energy scavenging from TYR and DGA in <i>Salmonella</i> involves TYR-oxidation via TYR-oxidoreductase and production of free-DGA via β-glucuronidase (GUS)-mediated hydrolysis of d-glucuronides (conjugated form of DGA), respectively. Here, we report that <i>Salmonella</i> utilizes TYR and DGA as sole sources of energy in a serotype-independent manner. Using colorimetric and radiometric approaches, we report that genes <i>SEN2971</i>, <i>SEN3065</i>, and <i>SEN2426</i> encode TYR-oxidoreductases. Some <i>Salmonella</i> serotypes produce GUS, thus can also scavenge energy from d-glucuronides. We repurposed phenelzine (monoaminoxidase-inhibitor) and amoxapine (GUS-inhibitor) to inhibit the TYR-oxidoreductases and GUS encoded by <i>Salmonella</i>, respectively. We show that phenelzine significantly inhibits the growth of <i>Salmonella</i> by inhibiting TYR-oxidoreductases SEN2971, SEN3065, and SEN2426. Similarly, amoxapine significantly inhibits the growth of <i>Salmonella</i> by inhibiting GUS-mediated hydrolysis of d-glucuronides. Because TYR and DGA serve as potential energy sources for <i>Salmonella</i> growth in vivo, the data and the novel approaches used here provides a better understanding of the role of TYR and DGA in <i>Salmonella</i> pathogenesis and nutritional virulence.
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