Authors

Discussion

Benzoxaboroles (BOBs) offer new opportunities for the pharmaceutical invention against a broad spectrum of infectious diseases including human and animal African trypanosomiasis.  CPSF3/CPSF73, the sole catalytic component of the pre-mRNA 3’-end cleavage and polyadenylation specific factor complex (CPSF), has been proposed as the primary target of BOBs in various protozoan pathogens, raising a possibility of common targeting mechanism.  We demonstrated a rapid increase in the global protein SUMOylation upon BOBs exposure as the key element of this potential common mode-of-action (MoA). Trypanosoma brucei developed cross-resistance to structurally diverse BOBs derivatives when the functions of the SUMOylation conjugation machinery were compromised through RNAi. This is in line with the result from our high throughput genetic screen (RIT-seq) uncovering the functional network underlying BOBs MoA. Importantly, the hyperSUMOylation triggered by BOBs leads to the destabilization of the TbCPSF complex in a proteosome-dependent manner, in parallel to changes in a cohort of surface proteins as well as a set of RNA-binding proteins (RBPs). Furthermore, we observed catastrophic nucleolar alterations specific to BOBs that may also lead to certain new insights into the common MoA of BOBs.