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Drug Discovery

Small molecule strikes hard-to-hit tuberculosis target

Structural information could help researchers create similar compounds in this class

by Bethany Halford
February 3, 2019 | A version of this story appeared in Volume 97, Issue 5


Structure of the small molecule 8918.

Fighting Mycobacterium tuberculosis can seem like an escalating arms race. The bacterium, which causes tuberculosis (TB), is a master at outmaneuvering drugs designed to kill it. Each year there are 450,000 new cases of TB that are resistant to multiple drugs, and nearly a third of TB-related deaths can be attributed to antimicrobial resistance. One TB target that scientists have long had in their sights is the enzyme phosphopantetheinyl transferase (PptT). PptT plays a role in the biosynthesis of mycolic acids that make up the bacterium’s cell wall and virulence lipids that the bacterium needs to suppress its hosts’ immune reactions. After years of trying, researchers have identified a compound that fights TB by inhibiting PptT. Known as 8918, the small molecule kills the bacterium in a petri dish and also prevents it from reproducing itself in the lungs of mice infected with TB. A team led by Weill Cornell Medicine’s Carl Nathan and Texas A&M University’s James Sacchettini made the discovery (Science 2019, DOI: 10.1126/science.aau8959). Using X-ray crystallography, the researchers were able to see how 8918 binds within PptT’s active site. Because 8918 is quickly metabolized, it’s not an ideal drug candidate. But the researchers hope the information they’ve gleaned from the crystal structure will help them design other compounds that inhibit PptT.


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