Phenelzine and Amoxapine Inhibit Tyramine and d-Glucuronic Acid Catabolism in Clinically Significant Salmonella in A Serotype-Independent Manner

Abstract

Non-typhoidal Salmonella 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 Salmonella 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 Salmonella utilizes TYR and DGA as sole sources of energy in a serotype-independent manner. Using colorimetric and radiometric approaches, we report that genes SEN2971, SEN3065, and SEN2426 encode TYR-oxidoreductases. Some Salmonella 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 Salmonella, respectively. We show that phenelzine significantly inhibits the growth of Salmonella by inhibiting TYR-oxidoreductases SEN2971, SEN3065, and SEN2426. Similarly, amoxapine significantly inhibits the growth of Salmonella by inhibiting GUS-mediated hydrolysis of d-glucuronides. Because TYR and DGA serve as potential energy sources for Salmonella growth in vivo, the data and the novel approaches used here provides a better understanding of the role of TYR and DGA in Salmonella pathogenesis and nutritional virulence.

Antimicrobial Properties of Antidepressants and Antipsychotics—Possibilities and Implications

“…Clorgyline, a MAOI, is active against C. albicans and C. glabrata where it inhibits efflux pumps and positively interacts with fluconazole [ 56 , 70 ]. A second MAOI, phenelzine, was found instead to be active against Salmonella [ 71 ]. Works based on TCAs showed that this class of molecules was active against Candida spp., where they inhibited hyphal formation, lysed the cells, and killed them even in a mature biofilm [ 72 , 73 ].…”

“…Works based on TCAs showed that this class of molecules was active against Candida spp., where they inhibited hyphal formation, lysed the cells, and killed them even in a mature biofilm [ 72 , 73 ]. Moreover, the TCA amoxapine is active against Salmonella and Y. pestis [ 54 , 71 ]. Interestingly, some TCAs and the antipsychotic thioridazine are capable to resensitize methicillin-resistant S. aureus (MRSA) to β-lactam [ 97 , 98 , 99 ].…”