Identification of kinase inhibitors as potential host-directed therapies for intracellular bacteria.

Autor: van den Biggelaar RHGA; Leiden University Center for Infectious Diseases, Leiden University Medical Center, Leiden, The Netherlands. r.h.g.a.van_den_biggelaar@lumc.nl.; Institute of Biology Leiden, Leiden University, Leiden, The Netherlands. r.h.g.a.van_den_biggelaar@lumc.nl., Walburg KV; Leiden University Center for Infectious Diseases, Leiden University Medical Center, Leiden, The Netherlands., van den Eeden SJF; Leiden University Center for Infectious Diseases, Leiden University Medical Center, Leiden, The Netherlands., van Doorn CLR; Leiden University Center for Infectious Diseases, Leiden University Medical Center, Leiden, The Netherlands., Meiler E; Global Health Medicines R&D, GlaxoSmithKline, Tres Cantos, Spain., de Ries AS; Institute of Biology Leiden, Leiden University, Leiden, The Netherlands., Fusco MC; Institute of Biology Leiden, Leiden University, Leiden, The Netherlands., Meijer AH; Institute of Biology Leiden, Leiden University, Leiden, The Netherlands., Ottenhoff THM; Leiden University Center for Infectious Diseases, Leiden University Medical Center, Leiden, The Netherlands., Saris A; Leiden University Center for Infectious Diseases, Leiden University Medical Center, Leiden, The Netherlands. a.saris@lumc.nl.
Jazyk: angličtina
Zdroj: Scientific reports [Sci Rep] 2024 Jul 26; Vol. 14 (1), pp. 17225. Date of Electronic Publication: 2024 Jul 26.
DOI: 10.1038/s41598-024-68102-6
Abstrakt: The emergence of antimicrobial resistance has created an urgent need for alternative treatments against bacterial pathogens. Here, we investigated kinase inhibitors as potential host-directed therapies (HDTs) against intracellular bacteria, specifically Salmonella Typhimurium (Stm) and Mycobacterium tuberculosis (Mtb). We screened 827 ATP-competitive kinase inhibitors with known target profiles from two Published Kinase Inhibitor Sets (PKIS1 and PKIS2) using intracellular infection models for Stm and Mtb, based on human cell lines and primary macrophages. Additionally, the in vivo safety and efficacy of the compounds were assessed using zebrafish embryo infection models. Our screen identified 11 hit compounds for Stm and 17 hit compounds for Mtb that were effective against intracellular bacteria and non-toxic for host cells. Further experiments were conducted to prioritize Stm hit compounds that were able to clear the intracellular infection in primary human macrophages. From these, two structurally related Stm hit compounds, GSK1379738A and GSK1379760A, exhibited significant activity against Stm in infected zebrafish embryos. In addition, we identified compounds that were active against intracellular Mtb, including morpholino-imidazo/triazolo-pyrimidinones that target PIK3CB, as well as 2-aminobenzimidazoles targeting ABL1. Overall, this study provided insights into kinase targets acting at the host-pathogen interface and identified several kinase inhibitors as potential HDTs.
(© 2024. The Author(s).)
Databáze: MEDLINE
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