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| Taifo Mahmud--Courtesy of Oregon State University |
As cases of drug-resistant tuberculosis rise worldwide, doctors have fewer effective options with which to treat patients. But scientists have successfully modified the precursor to one of the common antibacterial drugs used to treat tuberculosis, an important step toward developing new therapies that can treat this growing global health concern.
Researchers at Oregon State University, along with collaborators from the University of Delhi and the Institute of Genomics and Integrative Biology in India, have designed a new compound, 24-desmethylrifampicin, to have better antibacterial activity than rifampicin, a first-line drug used to treat tuberculosis and other infections. The findings are reported in The Journal of Biological Chemistry.
First-line drugs like rifampicin and others are the most effective drugs against tuberculosis. Some patients are resistant to first-line drugs, in which case, second-line drugs are necessary. Third-line drugs are used in rare cases and they may not be useful.
Rifampicin is often used alongside other drugs in a cocktail therapy that takes about six months of treatment to cure tuberculosis. But multi-drug-resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB) have become resistant to rifampicin and can take 18 months to several years to treat.
Drug resistance in rifampicin and related antibiotics occurs when the bacterial RNA polymerase enzymes mutate in the pathogen, explained Taifo Mahmud, a professor in the College of Pharmacy at Oregon State University and a corresponding author on the study, in a statement. When that happens, antibiotics that work by inhibiting RNA synthesis no longer work against the pathogen. But 24-desmethylrifampicin works by modifying the drug so it can effectively bind to this mutated enzyme and once again be effective.
"We found out how the antibiotic-producing bacteria make this compound, and then genetically modified that system to remove one part of the backbone of the molecule," Mahmud said. "Understanding this whole process should allow us to create not just this one, but a range of different analogs that can be tested for their efficacy as new antibiotics."
This new approach could help generate more analogs of rifamycin--the class of drugs rifampicin belongs to--to combat the threat of drug-resistant strains of tuberculosis, according to the investigators.
- see the study abstract
- read the press release