Old target, new mechanism for overcoming tuberculosis resistance

March 16, 2017

In strains of tuberculosis that have developed drug resistance mutations, researchers have identified a secondary pathway that can be activated to reinstate drug sensitivity. The rise of drug-resistant tuberculosis poses a serious threat to humans, with approximately 580,000 cases occurring in 2015, resulting in about 250,000 deaths. Current treatments against the tuberculosis-causing bacteria include prodrugs, such as ethionamide, which are activated by a bacterial enzyme. Ethionamide in particular is activated by the enzyme EthA, but some resistant forms of tuberculosis have developed mutations in the ethA gene, sparing them from the toxic effects of the transformed ethionamide. Building upon previous research to boost expression of EthA in resistant strains, Nicolas Blondiaux et al. suspected that an additional pathway for EthA production may exist. Here, they identified a small molecule, SMARt-420, that interacts with a secondary gene, which in turn stimulates expression of EthA. The team found that the combination of SMARt-420 and ethionamide was effective against a range of resistant tuberculosis strains. Mice infected with a resistant strain of tuberculosis that were treated with both SMARt-420 and ethionamide also showed a significantly reduced bacterial load in their lungs three weeks after infection compared to controls, the authors report.
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American Association for the Advancement of Science

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