|Title||20S proteasome as a drug target in Trichomonas vaginalis|
|Publication Type||Journal Article|
|Year of Publication||2019|
|Authors||O'Donoghue A.J, Bibo-Verdugo B., Miyamoto Y., Wang S.C, Yang J.Z, Zuill D.E, Matsuka S., Jiang Z.Z, Almaliti J., Caffrey C.R, Gerwick WH, Eckmann L.|
|Type of Article||Article|
|Keywords||delivery; design; disease; epidemiology; infection; irreversible inhibitor; metronidazole resistance; microbiology; pathway; Pharmacology & Pharmacy; proteasome; protozoa; substrate; Trichomonas vaginalis; validation|
Trichomoniasis is a sexually transmitted disease with hundreds of millions of annual cases worldwide. Approved treatment options are limited to two related nitro-heterocyclic compounds, yet resistance to these drugs is an increasing concern. New antimicrobials against the causative agent, Trichomonas vaginalis, are urgently needed. We show here that clinically approved anticancer drugs that inhibit the proteasome, a large protease complex with a critical role in degrading intracellular proteins in eukaryotes, have submicromolar activity against the parasite in vitro and on-target activity against the enriched T. vaginalis proteasome in cell-free assays. Proteomic analysis confirmed that the parasite has all seven alpha and seven beta subunits of the eukaryotic proteasome although they have only modest sequence identities, ranging from 28 to 52%, relative to the respective human proteasome subunits. A screen of proteasome inhibitors derived from a marine natural product, carmaphycin, revealed one derivative, carmaphycin-17, with greater activity against T. vaginalis than the reference drug metronidazole, the ability to overcome metronidazole resistance, and reduced human cytotoxicity compared to that of the anticancer proteasome inhibitors. The increased selectivity of carmaphycin-17 for T. vaginalis was related to its > 5-fold greater potency against the beta 1 and beta 5 catalytic subunits of the T. vaginalis proteasome than against the human proteasome subunits. In a murine model of vaginal trichomonad infection, proteasome inhibitors eliminated or significantly reduced parasite burden upon topical treatment without any apparent adverse effects. Together, these findings validate the proteasome of T. vaginalis as a therapeutic target for development of a novel class of trichomonacidal agents.