Editors' ChoiceTuberculosis

A New Drug on the Block

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Science Translational Medicine  14 Aug 2013:
Vol. 5, Issue 198, pp. 198ec136
DOI: 10.1126/scitranslmed.3007184

Tuberculosis (TB), caused by the bacterial pathogen Mycobacterium tuberculosis, causes substantial global illness and death each year. Of particular concern is the continued rise in infections due to multi- or extensively drug-resistant bacterial strains, demonstrating an urgent need for new effective drugs.

Pethe and colleagues screened more than 120,000 different compounds in a chemical library for inhibitors of M. tuberculosis growth within immune cells called macrophages. Through this screening method, the authors selected a compound that is a member of the imidazopyrimidine amides. They optimized this compound by synthesizing and evaluating 477 derivatives for their ability to block M. tuberculosis growth while not affecting eukaryotic cells. They derived a candidate drug called Q203 that was 100 times more potent than was the original compound, could inhibit drug-resistant strains, and had the potential to be synthesized on a large scale at low cost. Q203 did not kill eukaryotic cells and was found to be safe in mice and rats at both high and prolonged doses. In a mouse model of TB, mice treated with Q203 had reduced bacterial load and improved lung pathology comparable with that for other anti-TB drugs. Last, the authors sequenced rare strains of bacteria that were resistant to the new drug in order to elucidate its mechanism of action. Resistant strains had a mutation in a gene-coding part of the bacterial electron transport chain, which is necessary for bacterial synthesis of adenosine 5´-triphosphate (ATP), the chemical used for cellular energy production. To explore whether Q203 works by blocking ATP synthesis, the researchers measured ATP synthesis in bacterial cells in the presence of Q203 and other anti-TB drugs. Q203, but not the other anti-TB drugs, potently and rapidly inhibited ATP synthesis in bacterial cells.

This study demonstrates that candidate TB drugs with new mechanisms of action can be found through screening chemical libraries. It also supports exploring bacterial ATP synthesis as a new therapeutic target. Last, the discovery of a new anti-TB drug demonstrating a desirable safety and efficacy profile in cells and in a mouse model suggests that this candidate drug could be explored further for the treatment of drug-resistant TB. Multiple steps and ultimately human clinical trials are still necessary to determine whether this new drug will be safe and effective in humans suffering from TB.

K. Pethe et al., Discovery of Q203, a potent clinical candidate for the treatment of tuberculosis. Nat. Med., published online 4 August 2013 (10.1038/nm.3262). [Abstract]

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