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A Focused Screen Identifies Antifolates with Activity on Mycobacterium tuberculosis

Antifolates are widely used to treat several diseases but are not currently used in the first-line treatment of tuberculosis, despite evidence that some of these molecules can target Mycobacterium tuberculosis (Mtb) bacilli in vitro. To identify new antifolate candidates for animal-model efficacy st...

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Bibliographic Details
Published in:ACS infectious diseases 2015-12, Vol.1 (12), p.604-614
Main Authors: Kumar, Anuradha, Guardia, Ana, Colmenarejo, Gonzalo, Pérez, Esther, Gonzalez, Ruben R, Torres, Pedro, Calvo, David, Gómez, Ruben M, Ortega, Fátima, Jiménez, Elena, Gabarro, Raquel C, Rullás, Joaquín, Ballell, Lluis, Sherman, David R
Format: Article
Language:English
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Summary:Antifolates are widely used to treat several diseases but are not currently used in the first-line treatment of tuberculosis, despite evidence that some of these molecules can target Mycobacterium tuberculosis (Mtb) bacilli in vitro. To identify new antifolate candidates for animal-model efficacy studies of tuberculosis, we paired knowledge and tools developed in academia with the infrastructure and chemistry resources of a large pharmaceutical company. Together we curated a focused library of 2508 potential antifolates, which were then tested for activity against live Mtb. We identified 210 primary hits, confirmed the on-target activity of potent compounds, and now report the identification and characterization of 5 hit compounds, representative of 5 different chemical scaffolds. These antifolates have potent activity against Mtb and represent good starting points for improvement that could lead to in vivo efficacy studies.
ISSN:2373-8227
2373-8227
DOI:10.1021/acsinfecdis.5b00063