Amoxapine

Non‑typhoidal Salmonella can use host‑derived tyramine (TYR) and d‑glucuronic acid (DGA) as sole energy sources. The genes SEN2971, SEN3065, and SEN2426 encode TYR‑oxidoreductases; some serotypes also produce β‑glucuronidase (GUS) to release free DGA. The monoamine oxidase inhibitor phenelzine inhibited all three TYR‑oxidoreductases, blocking growth on TYR. The antidepressant amoxapine inhibited GUS, blocking growth on d‑glucuronides. Repurposing these approved drugs to disrupt Salmonella’s energy scavenging pathways offers a novel approach to combat nutritional virulence.

Fig. 1 TYR oxidoreductase activity of the recombinant SEN2971, SEN3065 and SEN2426, measured by a radiometric (a) and colorimetric assay (b). (Burin R, et al., 2021)

High‑throughput screening identified the tricyclic antidepressant amoxapine as a reducer of amyloid‑β production. Follow‑up studies revealed that most tricyclic antidepressants share this activity. Knockdown of serotonin receptor 6 (HTR6) reduced amoxapine’s effect, and the HTR6 antagonist SB258585 mimicked it. Mechanistically, amoxapine and SB258585 reduced Aβ through multiple HTR6‑mediated targets, including β‑arrestin2 and CDK5. Although amoxapine is no longer first‑line for depression, the authors propose that it, or structurally modified derivatives, could benefit Alzheimer’s disease, addressing both Aβ pathology and comorbid depression.

Fig. 2 Amoxapine, a typical secondary amine TCA, reduces Aβ generation in a dose-dependent manner. (Li X, et al., 2017)