An Old Antibiotic May Combat Drug-Resistant Tuberculosis

For decades, antibiotics have helped hold tuberculosis back, saving untold millions of lives. But their limits are being seriously tested as the bacterium’s tendency to mutate has led to a steady rise in drug-resistant strains. Without new drugs, scientists fear that tuberculosis, deemed largely a controllable disease, may not remain so. In search of new antibiotics, Rockefeller University scientists have landed on an existing compound, naturally produced by a bacterium. Their research, published online on November 16, 2020 in PNAS, elucidates how sorangicin A, first discovered in the 1980s, can destroy even the antibiotic-resistant bacteria that cause tuberculosis. The findings suggest that the compound may be a good candidate for further development as a first-line antibiotic for tuberculosis. The PNAS article is titled “The Antibiotic Sorangicin A Inhibits Promoter DNA Unwinding in a Mycobacterium tuberculosis Rifampicin-Resistant RNA Polymerase.” “Sorangicin inhibits regular strains in very much the same way as rifampin, one of the primary choices for tuberculosis antibiotics. But now we show that, through a different mechanism, it [sorangicin] also traps those variants that escape rifampin,” says Elizabeth Campbell, PhD, a Research Associate Professor at Rockefeller. The antibiotic rifampin works by blocking RNA polymerase (RNAP), an enzyme crucial to bacteria’s survival. This enzyme walks along a strand of DNA, using the genetic information to build an RNA molecule, one nucleotide at a time. Rifampin snaps into the cavity of one of RNAP’s pockets, and physically clogs the path of the RNA molecule when it’s no more than two or three nucleotides long. Without the proper RNA blueprints, the bacterium can’t make new proteins, and dies.
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