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Biological Chemistry

Lactones Block Waste Disposal In TB Bacteria

New lactones stop bacterial growth by blocking an enzyme that disposes of unneeded, damaged proteins—a target that current drugs don’t touch

September 30, 2013 | A version of this story appeared in Volume 91, Issue 39

Despite an arsenal of antibiotics, tuberculosis still kills more than 1 million people annually as it continually evolves resistance to the latest drugs. Now, researchers have identified a set of cyclic ester compounds known as β-lactones that show promise against Mycobacterium tuberculosis by targeting an enzyme it needs to survive but that current drugs don’t attack (ACS Chem. Biol. 2013, DOI: 10.1021/cb400577b). Corey L. Compton and Jason K. Sello of Brown University and colleagues tested 14 β-lactones on a nonpathogenic close relative of M. tuberculosis; four of them curbed bacterial growth. The team’s additional study on the two most potent compounds showed that they also inhibited the growth of M. tuberculosis. The researchers deduced through enzymatic assays that the new β-lactones probably work by reacting with ClpP, a TB enzyme that degrades and eliminates damaged or unneeded bacterial proteins. The most effective compound (shown) had potency similar to streptomycin, an antibiotic used to treat TB. The researchers believe the β-lactone’s potency stems from an aromatic benzyl group attached to the compound’s α-carbon. Although the β-lactone hasn’t been tested in animals, the researchers say the findings show ClpP’s viability as a target for developing drugs.


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