Inhibitors selective for mycobacterial versus human proteasomes

Gang Lin (), Dongyang Li, Luiz Pedro Sorio de Carvalho, Haiteng Deng, Hui Tao, Guillaume Vogt, Kangyun Wu, Jean Schneider, Tamutenda Chidawanyika, J. David Warren, Huilin Li () and Carl Nathan ()
Additional contact information
Gang Lin: Weill Cornell Medical College
Dongyang Li: Brookhaven National Laboratory, Upton, New York 11973-5000, USA
Luiz Pedro Sorio de Carvalho: Weill Cornell Medical College
Haiteng Deng: Proteomics Resource Center, The Rockefeller University, New York, New York 10065, USA
Hui Tao: Weill Cornell Medical College, New York, New York 10065, USA
Guillaume Vogt: Weill Cornell Medical College
Kangyun Wu: Weill Cornell Medical College
Jean Schneider: Weill Cornell Medical College
Tamutenda Chidawanyika: Weill Cornell Medical College
J. David Warren: Weill Cornell Medical College, New York, New York 10065, USA
Huilin Li: Brookhaven National Laboratory, Upton, New York 11973-5000, USA
Carl Nathan: Weill Cornell Medical College

Nature, 2009, vol. 461, issue 7264, 621-626

Abstract: 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.

Date: 2009
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DOI: 10.1038/nature08357

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