Even dormant bacteria need energy to live. Cutting off that energy supply for M.tb bacteria is the aim of a new TB drug discovery project being conducted by Prof. Harvey Rubin and his team at the University of Pennsylvania School of Medicine, Prof. Scott Franzblau and his team at the University of Illinois at Chicago, and the TB Alliance.
Drugs that target this energy-generation process should be good candidates for shortening TB therapy, as the length of current regimens is based largely on the need to eradicate the slow-growing, dormant populations of M.tb. And energy generation, says Rubin, "may be the Achilles heel of dormant bugs. Minimal as their energy needs may be, these dormant bugs still need to make ATP."
ATP is the energy currency of the cell. It is the culmination of a cellular game of pass-the-parcel, in which the parcels being passed are high energy electrons. Along this pathway, also called the "electron chain", the energy of these electrons is harvested and eventually turned into ATP.
An existing TB drug candidate, TMC-207, interferes with this final generation of ATP. But, says Rubin, "there is no doubt there are other parts of the pathway that are important." In fact, targeting the process nearer its start might be even more powerful. "If you can stop the bacterial cell from getting electrons into the chain," says Rubin, "so much the better."
Rubin's team will work out which parts of the pathway are most important and, with Franzblau's team, will develop tests in whole cells to find drugs that shut down the pathway. In parallel, the teams will also develop tests in which the whole electron-passing pathway is kept intact (in a greasy emulsion called a membrane), but is isolated from the rest of the cell.
With these tests, "we can look for drug candidates against not just a single target but the entire energy metabolism pathway," says Dr. Zhenkun Ma, Head of Research at the TB Alliance. "This will significantly improve our chances of finding a powerful drug candidate." Once the methods for the tests are established, the Chicago group will use them to screen large numbers of chemical compounds in the search for potential TB drugs.