Department of Microbiology and Immunology, Life Sciences Institute, University of British Columbia, Vancouver, BC, Canada
Joseph D. Chao
Department of Medicine, University of British Columbia, Vancouver, BC, Canada
Celine Rens
Department of Medicine, University of British Columbia, Vancouver, BC, Canada
Hasti Haghdadi
Department of Microbiology and Immunology, Life Sciences Institute, University of British Columbia, Vancouver, BC, Canada
Xingji Zheng
Department of Microbiology and Immunology, Life Sciences Institute, University of British Columbia, Vancouver, BC, Canada
Keegan Flanagan
Department of Microbiology and Immunology, Life Sciences Institute, University of British Columbia, Vancouver, BC, Canada
Mary Ko
Department of Medicine, University of British Columbia, Vancouver, BC, Canada
Tirosh Shapira
Department of Medicine, University of British Columbia, Vancouver, BC, Canada
Adrian Richter
Department of Medicine, University of British Columbia, Vancouver, BC, Canada; Institut für Pharmazie, Martin-Luther-Universität Halle-Wittenberg, Halle (Saale), Germany
Danay Maestre-Batlle
Department of Medicine, University of British Columbia, Vancouver, BC, Canada
Julio Ortiz Canseco
Host-pathogen Interactions in Tuberculosis Laboratory, The Francis Crick Institute, London, UK
Maximiliano Gabriel Gutierrez
Host-pathogen Interactions in Tuberculosis Laboratory, The Francis Crick Institute, London, UK
Khanh Dao Duc
Department of Mathematics, University of British Columbia, Vancouver, BC, Canada
Steven Pelech
Department of Medicine, University of British Columbia, Vancouver, BC, Canada; Kinexus Bioinformatics Corporation, 8755 Ash Street, Vancouver, BC, Canada
Yossef Av-Gay
Department of Microbiology and Immunology, Life Sciences Institute, University of British Columbia, Vancouver, BC, Canada; Department of Medicine, University of British Columbia, Vancouver, BC, Canada; Corresponding author
Summary: Compounds targeting host control of infectious diseases provide an attractive alternative to antimicrobials. A phenotypic screen of a kinase library identified compounds targeting glycogen synthase kinase 3 as potent inhibitors of Mycobacterium tuberculosis (Mtb) intracellular growth in the human THP-1 cell line and primary human monocytes-derived macrophages (hMDM). CRISPR knockouts and siRNA silencing showed that GSK3 isoforms are needed for the growth of Mtb and that a selected compound, P-4423632 targets GSK3β. GSK3 inhibition was associated with macrophage apoptosis governed by the Mtb secreted protein tyrosine phosphatase A (PtpA). Phospho-proteome analysis of macrophages response to infection revealed a wide array of host signaling and apoptosis pathways controlled by GSK3 and targeted by P-4423632. P-4423632 was additionally found to be active against other intracellular pathogens. Our findings strengthen the notion that targeting host signaling to promote the infected cell’s innate antimicrobial capacity is a feasible and attractive host-directed therapy approach.
