RNA Polymerase Inhibitors
RNA Polymerase (RNAP) is the enzyme that transcribes genetic information from DNA into RNA, which, in turn, directs the assembly of proteins that carry out most biological functions and are key structural components of cells. RNAP is a proven target for anti-tuberculosis therapies with the uncommon ability to kill both active and dormant M.tb when the enzyme is inhibited. A class of antibacterial compounds known as rifamycins, which also target RNAP, are used as part of the first-line treatment for TB and can rapidly reduce populations of M.tb to undetectable levels. When given at high dose, rifamycins can significantly shorten the standard duration of treatment in mouse TB models.
Unfortunately, the use of high dose rifamycins to rapidly clear infections is limited by their toxicity, and resistance to rifamycins occurs frequently due to mutations that alter their binding site on RNAP. A key goal of this program is to identify non-rifamycin, small molecule inhibitors of RNAP that can maximally inhibit the enzyme at clinically attainable doses and therefore shorten therapy. New drugs that function outside the rifamycin binding site on RNAP will be prioritized as these will likely be effective against rifamycin-resistant M.tb. Likewise, potent small molecule inhibitors may offer improvements in TB dosing regimens (improved pharmacokinetic profile relative to rifamycin), and delivery (opportunities for fixed dose combinations with other TB agents).