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Peña-Díaz S, Chao JD, Rens C, Haghdadi H, Zheng X, Flanagan K, Ko M, Shapira T, Richter A, Maestre-Batlle D, Canseco JO, Gutierrez MG, Duc KD, Pelech S, Av-Gay Y
iScience 27 (8) 110555 [2024-08-16; online 2024-07-20]
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.
Chemical Biology Consortium Sweden (CBCS) [Service]
PubMed 39175770
DOI 10.1016/j.isci.2024.110555
Crossref 10.1016/j.isci.2024.110555
pmc: PMC11340618
pii: S2589-0042(24)01780-2