Marta L. Lima, Lindsay B. Tulloch, Victoriano Corpas-Lopez, Sandra Carvalho, Richard J. Wall, Rachel Milne, Eva Rico, , Stephen Patterson, Ian H. Gilbert, Sonia Moniz, Lorna MacLean, Leah S. Torrie, Carmine Morgillo, David Horn, Fabio Zuccotto, Susan Wyllie.
Antimicrobial Agents and Chemotherapy 2022, Volume 66 Issue 1 e01535-21 https://doi.org/10.1128/AAC.01535-21
Phenotypic screening identified an arylsulfonamide compound with activity against Trypanosoma cruzi, the causative agent of Chagas’ disease. Comprehensive mode of action studies revealed that this compound primarily targets the T. cruzi proteasome, binding at the interface between b4 and b5 subunits that catalyze chymotrypsin- like activity. A mutation in the b5 subunit of the proteasome was associated with resistance to compound 1, while overexpression of this mutated subunit also reduced susceptibility to compound 1. Further genetically engineered and in vitroselected clones resistant to proteasome inhibitors known to bind at the b4/b5 interface were cross-resistant to compound 1. Ubiquitinated proteins were additionally found to accumulate in compound 1-treated epimastigotes. Finally, thermal proteome profiling identified malic enzyme as a secondary target of compound 1, although malic enzyme inhibition was not found to drive potency. These studies identify a novel pharmacophore capable of inhibiting the T. cruzi proteasome that may be exploitable for anti-chagasic drug discovery.