In:
Frontiers in Cellular and Infection Microbiology, Frontiers Media SA, Vol. 14 ( 2024-3-25)
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.
Type of Medium:
Online Resource
ISSN:
2235-2988
DOI:
10.3389/fcimb.2024.1367938
DOI:
10.3389/fcimb.2024.1367938.s001
DOI:
10.3389/fcimb.2024.1367938.s002
DOI:
10.3389/fcimb.2024.1367938.s003
DOI:
10.3389/fcimb.2024.1367938.s004
DOI:
10.3389/fcimb.2024.1367938.s005
DOI:
10.3389/fcimb.2024.1367938.s006
DOI:
10.3389/fcimb.2024.1367938.s007
DOI:
10.3389/fcimb.2024.1367938.s008
DOI:
10.3389/fcimb.2024.1367938.s009
DOI:
10.3389/fcimb.2024.1367938.s010
DOI:
10.3389/fcimb.2024.1367938.s011
DOI:
10.3389/fcimb.2024.1367938.s012
DOI:
10.3389/fcimb.2024.1367938.s013
Language:
Unknown
Publisher:
Frontiers Media SA
Publication Date:
2024
detail.hit.zdb_id:
2619676-1
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