A Focused Screen Identifies Antifolates with Activity on Mycobacterium tuberculosis

  • ACS Infect Dis. 2015 Dec 11;1(12):604-14. doi: 10.1021/acsinfecdis.5b00063.
Anuradha Kumar  1 ,  Ana Guardia  2 ,  Gonzalo Colmenarejo  3 ,  Esther Pérez  2 ,  Ruben R Gonzalez  2 ,  Pedro Torres  2 ,  David Calvo  2 ,  Ruben M Gómez  2 ,  Fátima Ortega  2 ,  Elena Jiménez  2 ,  Raquel C Gabarro  2 ,  Joaquín Rullás  2 ,  Lluis Ballell  2 ,  David R Sherman  1  4
Affiliations
  • 1. Center for Infectious Disease Research (Formerly Seattle Biomedical Research Institute) , Suite 500, Westlake Avenue North, Seattle, Washington 98109, United States.
  • 2. Diseases of the Developing World, GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Madrid, Spain.
  • 3. Centro de Investigación Básica, CSci Computational Chemistry, Platform Technologies and Science, Parque Tecnológico de Madrid , 28760 Tres Cantos, Madrid, Spain.
  • 4. Interdisciplinary Program of Pathobiology, Department of Global Health, University of Washington , Seattle, Washington 98195, United States.
PMID: 26771003 DOI: 10.1021/acsinfecdis.5b00063
Abstract

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.

Keywords
antifolate; dihydrofolate reductase; trimetrexate; tuberculosis.
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