Glycogen synthase kinase 3 inhibition controls Mycobacterium tuberculosis Infection

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.