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Sep 11, 2012

1950s NSAID Kills Resistant Tuberculosis

  • A cheap generic anti-inflammatory drug that’s been in use since the 1950s could represent a new weapon against drug-resistant tuberculosis, researchers suggest. Investigators at Weill Cornell Medical College, the Memorial Sloan Kettering Cancer Institute, Johns Hopkins University, and the Rockefeller University have found that the nonsteroidal anti-inflammatory drug oxyphenbutazone (OPB) is an effective antimycobacterial agent that displays potent activity against nonreplicating as well as replicating populations of the bacterium. Moreover, the drug has the added benefit of sensitizing the organism to existing drugs used to treat tuberculosis.

    Mycobacterium tuberculosis (Mtb) is notoriously hard to eradicate from an infected patient and typically requires months or potentially years’ of complex multidrug therapy, especially if drug resistance is evident. One of the reasons that the bacterium is so hard to kill off is that nonreplicating (NR) subpopulations that are tolerant to drugs persist in the patient.

    To try and identify compounds that may help address this drug-resistant population of NR Mtb as well as kill off replicating Mtb, the investigators carried out a high-throughput screen of over 5,600 existing pharmaceuticals, including synthetic compounds and those derived from bacterial and plant origins. The screen was carried out in two stages, to separately identify compounds effective against replicating Mtb, and also NR Mtb. The latter screen was effected on bacteria cultured under conditions that effectively halted replication, without affecting viability.

    The team found that OPB was up to 100% effective at inhibiting growth of NR Mtb, especially under conditions of low oxygen. In fact, it was under conditions that allow the bacterium to remain dormant that the drug is modified and becomes effective against both NR and replicating Mtb, the team explains. “When this happens, TB can’t defend itself and dies,” states lead Weill Cornell investigator Carl Nathan, M.D.

    Unfortunately, OPB can’t be tested in mice as a model of human disease because they metabolize the drug much faster than humans. This could represent a significant block to developing the drug for use against Mtb, even though it’s been on the market for years as anti-inflammatory. But there are indications that OPB could be an effective anti-mycobacterial in humans, the researchers write. They identified reports describing the use of OPB to treat the pain and fever associated with TB in 84 patients. These individuals were reported to demonstrate clearance of drug-resistant Mtb from sputum, faster weight gain, or improved tolerance to conventional therapy.

    And although OPB does have some potential side effects, the magnitude of these are likely to be acceptable when compared with the toxicity of second-line TB therapies, and what the researchers call the dire prognosis of patients with drug-resistant TB. Moreover, many patients who need to move on to second-line therapy for drug-resistant TB won’t receive the treatment they need because the drugs are just too expensive. In contrast, OPB is exceedingly cheap.

    However, the researchers write, initiating trials of OPB against tuberculosis will be an uphill struggle. “It is difficult to launch clinical studies on a medication that is so outdated in the U.S. that it is mainly used here in veterinary medicine to ease pain,” Dr. Nathan notes. “No drug firm will pay for clinical trials if they don’t expect to make a profit on the agent. And that would be the case for an off-patent drug that people can buy over the counter for pain in most of the world.”

    The investigators describe their findings in PNAS in a paper titled “Nonsteroidal antiinflammatory drug sensitizes Mycobacterium tuberculosis to endogenous and exogenous antimicrobials.” 


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