The Global Alliance for TB Drug Development (TB Alliance) and Rutgers, The State University of New Jersey announced a collaboration to identify new small-molecule inhibitors of Mycobacterium tuberculosis RNA polymerase (RNAP) with the intent of developing new and improved TB treatments. The partnership will enable the TB Alliance to work with a research team led by Rutgers Professor and Howard Hughes Medical Institute Investigator, Dr. Richard Ebright.
Dr. Ebright and colleagues have identified new antibiotic targets and mechanisms that may enable the development of broad-spectrum antibacterial agents effective against pathogens resistant to current antibiotics. Dr. Ebright and colleagues also have developed methods to produce large quantities of highly pure, highly active, Mycobacterium tuberculosis RNAP. This work has generated optimism regarding its potential to lead to new treatments for TB that could shorten the standard treatment regimen and be effective against resistant strains of the disease
"The partnership between Rutgers and the TB Alliance represents a valuable opportunity to intensify and accelerate the exploration of RNA polymerase as a drug target with a focus on improving TB treatment regimens," said Dr. Zhenkun Ma, Head of Research, TB Alliance. "We are excited to be a part of this work and optimistic about its potential to yield compounds that will ultimately be valuable weapons against the global burden of tuberculosis."
RNAP is a proven target for anti-tuberculosis therapy with the uncommon ability to kill both active and dormant TB bacteria when the enzyme is inhibited. A class of antibacterial compounds known as rifamycins, which also target RNAP, are used as first-line treatment of TB and are the only current treatments that can relatively rapidly reduce populations of TB bacteria to undetectable levels. When given at high dose, rifamycins can significantly shorten 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 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 tuberculosis bacteria.