Oxathiazole-2-one is a new candidate for proteasome inhibition which has not been widely explored. We describe herein the synthesis and characterization of a new oxathiazole-2-one derived from the dipeptide backbone of Bortezomib. We found that this new oxathiazole-2-one compound 1 is modestly active against the human 20S proteasome, but surprisingly has no significant activity against the M. tuberculosis proteasome. Additionally, the compound has improved aqueous stability compared to previously reported oxathiazole-2-one compounds. Molecular docking analyses provided information on the structural basis of the observed disparity between the human and mycobacterium proteasomes inhibitory activity of compound 1. © 2011 The Royal Society of Chemistry.