Infection Control Today (09.18.2013)
Aids Weekly Plus
Researchers at Brown University in Providence, R.I., and the Massachusetts Institute of Technology (MIT) have found a different way of destroying the TB bacteria by inhibiting an essential enzyme in the bacteria called ClpP, which is not targeted by any existing antibacterial drug.
Since ß-lactones were known to inhibit ClpP in other bacteria, the researchers synthesized 14 ß-lactones, each with a slightly different structure, and tested them against Mycobacterium smegmatis, a relative of TB that does not cause disease. Of the 14 molecules, four killed M. smegmatis. The researchers then sent the molecules to the Institute for TB Research at the University of Illinois for additional testing. The result was that the compounds also destroyed M. tuberculosis. Of the 14, the most potent was ß-lactone 7, whose structure was different from that of other known ClpP inhibitors. It was found to have a potency similar to that of streptomycin, an antituberculosis drug.
The researchers then needed to confirm that the compounds were destroying the bacteria by inhibiting ClpP. MIT researchers tested the activity of ClpP using an in vitro assay and proved that when ClpP was treated with ß-lactone, the enzyme was inhibited. Results suggested that molecules that inhibit ClpP might be important in finding new drugs to fight TB. Jason Sello, associate professor of chemistry at Brown University and lead researcher, concluded that the data showed ClpP was a viable antibacterial drug target and that inactivating ClpP would stop the growth of the TB bacterium.
The full report, “Antibacterial Activity of and Resistance to Small Molecule Inhibitors of the ClpP Peptidase,” was published online in the journal ACS Chemical Biology (2013; doi: 10.1021/cb400577b).