New Tuberculosis Drug Target

The proteasome—the cell’s garbage disposal for proteins—could become a target for new tuberculosis drugs, biologists report. A team led by Carl Nathan of Weill Cornell Medical College has found that some oxathiazolone compounds kill tuberculosis-causing bacteria by selectively inhibiting mycobacterial proteasomes without affecting human proteasomes (Nature, DOI: 10.1038/nature08357).

Mycobacterium tuberculosis is one of the few bacterial species with a proteasome, a cellular machine that degrades proteins that cells have marked for destruction. Proteasomes are found in all eukaryotic cells, including human cells. The antibacterial compounds are the first example of an anti-infective agent that inhibits protein breakdown. Many such drugs block protein synthesis.

Earlier, Nathan’s team showed that a proteasome inhibitor used as an anticancer agent kills M. tuberculosis. But that drug was too toxic to be used as an anti-infective agent. “Our goal became to see whether we could exploit subtle differences between bacterial proteasomes and human proteasomes to make a selective inhibitor,” Nathan says.

Now, Nathan’s team has discovered oxathiazolones, such as one called GL5, that inhibit the mycobacterial proteasome without affecting the human proteasome. They were encouraged in their search for species-selective inhibitors by the subtle differences between GL5 and GL6, an inactive compound. “The changes are very small,” yet the activity of the two compounds is “all or nothing,” Nathan says.

The inhibitors attach to a threonine residue in the proteasome’s active site. When an inhibitor binds to the mycobacterial proteasome, a conformational change in the proteasome enables the inhibitor-enzyme intermediate to undergo an irreversible cyclocarbonylation, Nathan says. The reaction shuts down proteasome activity.

With the human proteasome, water hydrolyzes the inhibitor-enzyme intermediate and prevents the proteasome-inhibiting reaction. “The oxathiazolone is a simple substrate for the human proteasome, but it’s a suicide-substrate inhibitor for the TB proteasome,” he says.

Commenting on the work, John S. Blanchard of Albert Einstein College of Medicine, in Bronx, N.Y., notes that crystal structures obtained by Nathan and coworkers indicate significant structural rearrangement in an area of low sequence similarity between the mycobacterial and human proteasomes. “This suggests that additional specificity determinants can be built into subsequent generations of inhibitors,” he says.

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