A Focused Screen Identifies Antifolates with Activity on Mycobacterium tuberculosis

ACS Infectious Diseases
Anuradha KumarDavid R Sherman

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.

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Citations

May 25, 2016·Biochimica Et Biophysica Acta. General Subjects·Kinga Nyíri, Beáta G Vértessy
Jul 18, 2018·Antimicrobial Agents and Chemotherapy·Adrian RichterYossef Av-Gay
Jul 16, 2019·MedChemComm·Shannon Lynn Kordus, Anthony David Baughn
Feb 20, 2021·Frontiers in Microbiology·Alina MiniasJarosław Dziadek
Mar 24, 2021·Journal of Enzyme Inhibition and Medicinal Chemistry·Alexia de Matos CzeczotCristiano Valim Bizarro
May 29, 2021·RSC Medicinal Chemistry·Gustavo P RiboldiBart L Staker
Jun 10, 2017·Microbiology Spectrum·Michael Berney, Linda Berney-Meyer
Jun 24, 2021·Proceedings of the National Academy of Sciences of the United States of America·Wassihun Wedajo AragawThomas Dick

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