A Focused Screen Identifies Antifolates with Activity on Mycobacterium tuberculosis

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• 作者：Anuradha Kumar ; Ana Guardia ; Gonzalo Colmenarejo ; Esther Pérez ; Ruben R. Gonzalez ; Pedro Torres ; David Calvo ; Ruben M. Gómez ; Fátima Ortega ; Elena Jiménez ; Raquel C. Gabarro ; Joaquín Rullás ; Lluis Ballell ; David R. Sherman
• 刊名：ACS Infectious Diseases
• 出版年：2015
• 出版时间：December 11, 2015
• 年：2015
• 卷：1
• 期：12
• 页码：604-614
• 全文大小：520K
• ISSN：2373-8227

文摘

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.