Novel sulfatase cancer therapeutics negatively impact Bacteroidota of the colonic microbiota in a non-sulfatase dependent manner

Abstract

AbstractThe S1 family of sulfatases is the sole family of enzymes that desulfate carbohydrates, linking them to inflammatory bowel diseases and various cancers. There is an unmet need for therapeutics against carbohydrate sulfatases, and while effective, orally available inhibitors of S1 steroid sulfatases exist, their efficacy against S1 carbohydrate sulfatases remains largely unexplored. In this study we assess a library of aryl- and carbohydrate sulfamates/sulfonates for their ability to inhibit carbohydrate sulfatases from human colonic bacteria. Surprisingly, these compounds prove ineffective. We show that arylsulfamate inhibitors inhibit the growth of anti-cancer human gut microbiota species independent of sulfatase activity. Leveraging thermal proteome profiling, we identify the non-sulfatase targets responsible for these effects. This work highlights the imperative for developing specific inhibitors targeting carbohydrate sulfatases and unveils the adverse effects of arylsulfamates, a class of drugs designed for hormone cancer treatment, on the human gut microbiota, potentially influencing their therapeutic efficacy.