title: A Focused Screen Identifies Antifolates with Activity on Mycobacterium tuberculosis.
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.
authors.affiliation: Center for Infectious Disease Research (Formerly Seattle Biomedical Research Institute) , Suite 500, Westlake Avenue North, Seattle, Washington 98109, United States.
authors.forename: Anuradha
authors.initials: A
authors.lastname: Kumar
authors.affiliation: Diseases of the Developing World, GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Madrid, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Guardia
authors.affiliation: Centro de Investigación Básica, CSci Computational Chemistry, Platform Technologies and Science, Parque Tecnológico de Madrid , 28760 Tres Cantos, Madrid, Spain.
authors.forename: Gonzalo
authors.initials: G
authors.lastname: Colmenarejo
authors.affiliation: Diseases of the Developing World, GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Madrid, Spain.
authors.forename: Esther
authors.initials: E
authors.lastname: Pérez
authors.affiliation: Diseases of the Developing World, GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Madrid, Spain.
authors.forename: Ruben R
authors.initials: RR
authors.lastname: Gonzalez
authors.affiliation: Diseases of the Developing World, GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Madrid, Spain.
authors.forename: Pedro
authors.initials: P
authors.lastname: Torres
authors.affiliation: Diseases of the Developing World, GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Madrid, Spain.
authors.forename: David
authors.initials: D
authors.lastname: Calvo
authors.affiliation: Diseases of the Developing World, GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Madrid, Spain.
authors.forename: Ruben M
authors.initials: RM
authors.lastname: Gómez
authors.affiliation: Diseases of the Developing World, GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Madrid, Spain.
authors.forename: Fátima
authors.initials: F
authors.lastname: Ortega
authors.affiliation: Diseases of the Developing World, GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Madrid, Spain.
authors.forename: Elena
authors.initials: E
authors.lastname: Jiménez
authors.affiliation: Diseases of the Developing World, GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Madrid, Spain.
authors.forename: Raquel C
authors.initials: RC
authors.lastname: Gabarro
authors.affiliation: Diseases of the Developing World, GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Madrid, Spain.
authors.forename: Joaquín
authors.initials: J
authors.lastname: Rullás
authors.affiliation: Diseases of the Developing World, GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Madrid, Spain.
authors.forename: Lluis
authors.initials: L
authors.lastname: Ballell
authors.affiliation: Center for Infectious Disease Research (Formerly Seattle Biomedical Research Institute) , Suite 500, Westlake Avenue North, Seattle, Washington 98109, United States.|Interdisciplinary Program of Pathobiology, Department of Global Health, University of Washington , Seattle, Washington 98195, United States.
authors.forename: David R
authors.initials: DR
authors.lastname: Sherman
keywords: antifolate; dihydrofolate reductase; trimetrexate; tuberculosis