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

Abstract

The emergence of antimicrobial resistance has created an urgent need for alternative treatment strategies against deadly bacterial species. In this study, we investigated the potential of kinase inhibitors as host-directed therapies (HDTs) for combating infectious diseases caused by 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 efficacy of the compounds was assessed using zebrafish embryo infection models. Our kinase inhibitor screen identified 14 hit compounds for Stm and 19 hit compounds for Mtb that were effective against intracellular bacteria and non-toxic for host cells. Further validation experiments showed the high efficacy of most Stm hit compounds and their ability to fully clear the intracellular infection both in cell lines and primary human macrophages. From these, two structurally related Stm hit compounds, GSK1379738A and GSK1379760A, exhibited significant effectiveness against Stm in infected zebrafish embryos. Compounds that were active against intracellular Mtb included morpholino-imidazo/triazolo-pyrimidinones that specifically target the kinases PIK3CB and PIK3CD as well as 2-aminobenzimidazoles targeting BLK, ABL1 and TRKA. Overall, this study provided insight into critical kinase targets acting at the host-pathogen interface and identified novel kinase inhibitors as potential HDTs for intracellular bacterial infections.