Host-directed kinase inhibitors act as novel therapies against intracellular Staphylococcus aureus View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2019-12

AUTHORS

Natalia Bravo-Santano, Helen Stölting, Frederic Cooper, Narina Bileckaja, Andrea Majstorovic, Nadine Ihle, Luis M. Mateos, Yolanda Calle, Volker Behrends, Michal Letek

ABSTRACT

Host-directed therapeutics are a promising anti-infective strategy against intracellular bacterial pathogens. Repurposing host-targeted drugs approved by the FDA in the US, the MHRA in the UK and/or regulatory equivalents in other countries, is particularly interesting because these drugs are commercially available, safe doses are documented and they have been already approved for other clinical purposes. In this study, we aimed to identify novel therapies against intracellular Staphylococcus aureus, an opportunistic pathogen that is able to exploit host molecular and metabolic pathways to support its own intracellular survival. We screened 133 host-targeting drugs and found three host-directed tyrosine kinase inhibitors (Ibrutinib, Dasatinib and Crizotinib) that substantially impaired intracellular bacterial survival. We found that Ibrutinib significantly increased host cell viability after S. aureus infection via inhibition of cell invasion and intracellular bacterial proliferation. Using phosphoproteomics data, we propose a putative mechanism of action of Ibrutinib involving several host factors, including EPHA2, C-JUN and NWASP. We confirmed the importance of EPHA2 for staphylococcal infection in an EPHA2-knock-out cell line. Our study serves as an important example of feasibility for identifying host-directed therapeutics as candidates for repurposing. More... »

PAGES

4876

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/s41598-019-41260-8

DOI

http://dx.doi.org/10.1038/s41598-019-41260-8

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1112853136

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/30890742


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