PUBLICATION
Identification of kinase modulators as host-directed therapeutics against intracellular methicillin-resistant Staphylococcus aureus
- Authors
- van den Biggelaar, R.H.G.A., Walburg, K.V., van den Eeden, S.J.F., van Doorn, C.L.R., Meiler, E., de Ries, A.S., Meijer, A.H., Ottenhoff, T.H.M., Saris, A.
- ID
- ZDB-PUB-240409-9
- Date
- 2024
- Source
- Frontiers in cellular and infection microbiology 14: 13679381367938 (Journal)
- Registered Authors
- Meijer, Annemarie H.
- Keywords
- AMPK, EGFR/HER kinase family, autophagy, host-directed therapy, intracellular infection, methicillin-resistant Staphylococcus aureus, published kinase inhibitor set (PKIS), zebrafish embryo
- MeSH Terms
-
- Animals
- Anti-Bacterial Agents/pharmacology
- Anti-Bacterial Agents/therapeutic use
- Humans
- Methicillin-Resistant Staphylococcus aureus*
- Microbial Sensitivity Tests
- Staphylococcal Infections*/microbiology
- Staphylococcus aureus
- Zebrafish
- PubMed
- 38590439 Full text @ Front Cell Infect Microbiol
Citation
van den Biggelaar, R.H.G.A., Walburg, K.V., van den Eeden, S.J.F., van Doorn, C.L.R., Meiler, E., de Ries, A.S., Meijer, A.H., Ottenhoff, T.H.M., Saris, A. (2024) Identification of kinase modulators as host-directed therapeutics against intracellular methicillin-resistant Staphylococcus aureus. Frontiers in cellular and infection microbiology. 14:13679381367938.
Abstract
The increasing prevalence of antimicrobial-resistant Staphylococcus aureus strains, especially methicillin-resistant S. aureus (MRSA), poses a threat to successful antibiotic treatment. Unsuccessful attempts to develop a vaccine and rising resistance to last-resort antibiotics urge the need for alternative treatments. Host-directed therapy (HDT) targeting critical intracellular stages of S. aureus emerges as a promising alternative, potentially acting synergistically with antibiotics and reducing the risk of de novo drug resistance. We assessed 201 ATP-competitive kinase inhibitors from Published Kinase Inhibitor Sets (PKIS1 and PKIS2) against intracellular MRSA. Seventeen hit compounds were identified, of which the two most effective and well-tolerated hit compounds (i.e., GW633459A and GW296115X) were selected for further analysis. The compounds did not affect planktonic bacterial cultures, while they were active in a range of human cell lines of cervical, skin, lung, breast and monocyte origin, confirming their host-directed mechanisms. GW633459A, structurally related to lapatinib, exhibited an HDT effect on intracellular MRSA independently of its known human epidermal growth factor receptor (EGFR)/(HER) kinase family targets. GW296115X activated adenosine monophosphate-activated protein kinase (AMPK), thereby enhancing bacterial degradation via autophagy. Finally, GW296115X not only reduced MRSA growth in human cells but also improved the survival rates of MRSA-infected zebrafish embryos, highlighting its potential as HDT.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping