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Updated: Jun 29, 2025
Biosensor for Detection of Antibiotic Resistant Staphylococcus Bacteria
Published on: May 8, 2013
Identification of kinase modulators as host-directed therapeutics against intracellular methicillin-resistant
Robin H G A van den Biggelaar1,2, Kimberley V Walburg1, Susan J F van den Eeden1
1Leiden University Center for Infectious Diseases, Leiden University Medical Center, Leiden, Netherlands.
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.
Insights
Host-directed therapy offers a novel approach against drug-resistant Staphylococcus aureus. Researchers identified kinase inhibitors that target intracellular MRSA, showing promise for new treatments when antibiotics fail.
Area of Science:
- Microbiology
- Pharmacology
- Infectious Diseases
Background:
- Antimicrobial resistance in Staphylococcus aureus, particularly MRSA, necessitates alternative therapeutic strategies.
- Vaccine development has been unsuccessful, and resistance to last-resort antibiotics is rising.
- Host-directed therapy (HDT) presents a promising alternative by targeting intracellular bacterial stages.
Purpose of the Study:
- To identify host-directed compounds effective against intracellular methicillin-resistant Staphylococcus aureus (MRSA).
- To evaluate the efficacy and mechanism of action of identified compounds.
- To assess the therapeutic potential of lead compounds in preclinical models.
Main Methods:
- Screening of 201 ATP-competitive kinase inhibitors from PKIS1 and PKIS2 against intracellular MRSA.
- Testing hit compounds in various human cell lines and planktonic cultures.
- Investigating mechanisms of action, including EGFR/HER and AMPK pathways, and evaluating efficacy in zebrafish embryos.
Main Results:
- Seventeen hit compounds were identified, with GW633459A and GW296115X selected for further study.
- Hit compounds demonstrated host-directed activity in human cell lines but not in planktonic cultures.
- GW633459A showed HDT effects independent of EGFR/HER targets; GW296115X activated AMPK, enhancing autophagy-mediated bacterial degradation.
Conclusions:
- Kinase inhibitors can serve as effective host-directed therapies against intracellular MRSA.
- GW296115X demonstrates potential as an anti-MRSA therapeutic by modulating host cell pathways and improving survival in vivo.
- HDT represents a viable strategy to combat challenging MRSA infections.
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