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.
Highlights
Staphylococcus aureus is a facultative intracellular pathogen carried by about 40% of the population in their nasal passages[1]
Using a two-fold cut-off of a 90% reduction of intracellular methicillin-resistant S. aureus (MRSA) compared to the untreated host cells and a host cell viability of at least 80% compared to uninfected host cells, we identified three drugs meeting these criteria: Ibrutinib, Dasatinib and Crizotinib (Fig. 2B; for results of all drugs, see Table S1)
We identified several kinases that belong to MEK/ERK pathway (MEK2, ERK1/2/7, RSK2 and p90RSK) and three c-Jun N-Terminal kinases (JNK1/2/3; Fig. S4), which reflects the importance of MEK/ERK/c-JUN signalling for intracellular S. aureus survival and proliferation
Summary
Staphylococcus aureus is a facultative intracellular pathogen carried by about 40% of the population in their nasal passages[1]. Host cell invasion and intracellular survival could be used by S. aureus to infect macrophages, spread to secondary points of infection, evade immune recognition, and avoid exposure to last-resort antibiotics such as vancomycin[7]. This is important for hospital-acquired infections with the methicillin-resistant S. aureus (MRSA). Novel anti-infective strategies are urgently needed against this versatile pathogen to complement traditional antibiotherapy As part of their host-defense evasion mechanism, intracellular pathogens subvert and exploit a wide range of host factors and pathways to support their intracellular survival[8], targeting multiple pathways to assure their intracellular proliferation[9]. Cholesterol biosynthesis inhibition has shown potential against S. aureus since it is needed for the internalization of the bacteria and the activation of virulence factors[12,16]
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