Inhibitors Selective for Mycobacterial versus Human Proteasomes

Department of Microbiology and Immunology, Weill Cornell Medical College, New York, New York 10065, USA.
Nature (Impact Factor: 42.35). 09/2009; 461(7264):621-6. DOI: 10.1038/nature08357
Source: PubMed

ABSTRACT Many anti-infectives inhibit the synthesis of bacterial proteins, but none selectively inhibits their degradation. Most anti-infectives kill replicating pathogens, but few preferentially kill pathogens that have been forced into a non-replicating state by conditions in the host. To explore these alternative approaches we sought selective inhibitors of the proteasome of Mycobacterium tuberculosis. Given that the proteasome structure is extensively conserved, it is not surprising that inhibitors of all chemical classes tested have blocked both eukaryotic and prokaryotic proteasomes, and no inhibitor has proved substantially more potent on proteasomes of pathogens than of their hosts. Here we show that certain oxathiazol-2-one compounds kill non-replicating M. tuberculosis and act as selective suicide-substrate inhibitors of the M. tuberculosis proteasome by cyclocarbonylating its active site threonine. Major conformational changes protect the inhibitor-enzyme intermediate from hydrolysis, allowing formation of an oxazolidin-2-one and preventing regeneration of active protease. Residues outside the active site whose hydrogen bonds stabilize the critical loop before and after it moves are extensively non-conserved. This may account for the ability of oxathiazol-2-one compounds to inhibit the mycobacterial proteasome potently and irreversibly while largely sparing the human homologue.

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Available from: J David Warren, Jul 28, 2015
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    • "These results are in agreement with those of earlier studies in E. coli (Hyduke et al., 2007; Ren et al., 2008). Earlier DETA-NO was used to create a nitro-oxidative stress that limits the replication of M. tuberculosis (Lin et al., 2009). "
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    • "Genes that are up-regulated during the chronic phase of infection and their corresponding proteins offer a unique avenue for drug design that would allow treatment of latent TB infections. Recently, mycobacterial-specific inhibitors of the Mtb proteasome, oxathiazol-2-one compounds, have been identified that kill non-replicating Mtb (Lin et al., 2009). These compounds act similarly to human proteasome drugs by acting as suicide-substrate inhibitors via cyclocarbonylation of the proteasome active site threonine. "
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