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Proteasomes are large protein complexes that are structurally conserved across eukaryote cells including mycobacteria. They are needed to degrade unneeded or damaged proteins and, as such, have a vital role in cellular homeostasis. The cytotoxicity of proteasome inhibitors has been demonstrated by bortezomib (Velcade), which was the first therapeutic proteasome inhibitor and is licensed for use against multiple myeloma. Unfortunately, non-selective proteasome inhibitors are inherently toxic, limiting their potential use. In the present study the authors screened over 20 000 compounds to identify two oxathiazol-2-one inhibitors—GL5 and HT117—that were able to cross the cell wall of Mycobacterium tuberculosis and inhibit proteasome activity. These compounds were compared with bortezomib for efficacy and toxicity. Measured against the BCG strain, at equal concentrations GL5 and HT117 inhibited around 90% of mycobacterial proteasome activity compared with 52% achieved by bortezomib. Both compounds dose-dependently killed M tuberculosis over 4 days in synergy with nitric oxide (which at sub-lethal levels renders M tuberculosis non-replicative). Furthermore, GL5 and HT117 were non-toxic to mammalian cells when given at concentrations 3000-fold greater than those at which bortezomib killed monkey epithelial cells. In kinetic studies, oxathiazol-2-one compounds inhibited M tuberculosis proteasomes irreversibly.
Non-replicating M tuberculosis displays relative resistance to conventional antibiotics. Mycobactericidal, non-cytotoxic proteasome inhibitors that act irreversibly may provide a novel therapeutic tool against M tuberculosis as well as a synergistic adjunct to conventional anti-tuberculosis medications.
▶ Lin G, Li D, Sorio de Carvalho LP, et al. Inhibitors selective for mycobacterial versus human proteasomes. Nature 2009;461:621–6.