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Old target, new mechanism for overcoming tuberculosis resistance

Date:
March 16, 2017
Source:
American Association for the Advancement of Science
Summary:
In strains of tuberculosis that have developed drug resistance mutations, researchers have identified a secondary pathway that can be activated to reinstate drug sensitivity.
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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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Journal Reference:

  1. Nicolas Blondiaux, Martin Moune, Matthieu Desroses, Rosangela Frita, Marion Flipo, Vanessa Mathys, Karine Soetaert, Mehdi Kiass, Vincent Delorme, Kamel Djaout, Vincent Trebosc, Christian Kemmer, René Wintjens, Alexandre Wohlkönig, Rudy Antoine, Ludovic Huot, David Hot, Mireia Coscolla, Julia Feldmann, Sebastien Gagneux, Camille Locht, Priscille Brodin, Marc Gitzinger, Benoit Déprez, Nicolas Willand, Alain R. Baulard. Reversion of antibiotic resistance in Mycobacterium tuberculosis by spiroisoxazoline SMARt-420. Science, 2017; 355 (6330): 1206 DOI: 10.1126/science.aag1006

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American Association for the Advancement of Science. "Old target, new mechanism for overcoming tuberculosis resistance." ScienceDaily. ScienceDaily, 16 March 2017. <www.sciencedaily.com/releases/2017/03/170316141035.htm>.
American Association for the Advancement of Science. (2017, March 16). Old target, new mechanism for overcoming tuberculosis resistance. ScienceDaily. Retrieved May 25, 2017 from www.sciencedaily.com/releases/2017/03/170316141035.htm
American Association for the Advancement of Science. "Old target, new mechanism for overcoming tuberculosis resistance." ScienceDaily. www.sciencedaily.com/releases/2017/03/170316141035.htm (accessed May 25, 2017).

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