{"doi":"10.3389/fcimb.2024.1367938","title":"Identification of kinase modulators as host-directed therapeutics against intracellular methicillin-resistant Staphylococcus aureus","abstract":"<jats:p>The increasing prevalence of antimicrobial-resistant <jats:italic>Staphylococcus aureus</jats:italic> strains, especially methicillin-resistant <jats:italic>S. aureus</jats:italic> (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 <jats:italic>S. aureus</jats:italic> emerges as a promising alternative, potentially acting synergistically with antibiotics and reducing the risk of <jats:italic>de novo</jats:italic> 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.</jats:p>","journal":"Frontiers in Cellular and Infection Microbiology","year":2024,"id":612734,"datarank":0.32958368660043297,"base_score":2.1972245773362196,"endowment":2.1972245773362196,"self_citation_contribution":0.32958368660043297,"citation_network_contribution":0.0,"self_endowment_contribution":0.32958368660043297,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":8,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1577810,"name":"Kimberley V. 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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.</jats:p>","is_dataset_classified":null,"base_score":2.1972245773362196,"endowment":2.1972245773362196,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"38590439","pmcid":"PMC10999543","openalex_id":"https://openalex.org/W4393156626","authors":[],"funders":[{"funder_name":"Nederlandse Organisatie voor Wetenschappelijk Onderzoek","grant_id":"16444","title":"Chemical genetics to target intracellular drug-resistant bacteria."}],"total_grants":1,"fwci":2.4455,"citation_percentile":0.88920637,"influential_citations":0,"citation_trend":[{"year":2024,"count":3},{"year":2025,"count":5}],"oa_status":"gold","license":"cc-by","oa_locations":[{"url":"https://www.frontiersin.org/articles/10.3389/fcimb.2024.1367938/pdf?isPublishedV2=False","host_type":"journal"},{"url":"https://www.frontiersin.org/articles/10.3389/fcimb.2024.1367938/pdf?isPublishedV2=False","host_type":"publisher"},{"url":"https://www.frontiersin.org/articles/10.3389/fcimb.2024.1367938/full","host_type":"publisher"},{"url":"https://doi.org/10.3389/fcimb.2024.1367938","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/38590439","host_type":"repository"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/10999543","host_type":"repository"},{"url":"https://doaj.org/article/d4a0576083104c598b9a431663c54c44","host_type":"repository"},{"url":"https://hdl.handle.net/1887/3753913","host_type":"repository"},{"url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC10999543/pdf/fcimb-14-1367938.pdf","host_type":"repository"},{"url":"https://europepmc.org/articles/PMC10999543","host_type":"Europe_PMC"},{"url":"https://europepmc.org/articles/PMC10999543?pdf=render","host_type":"Europe_PMC"},{"url":"http://dx.doi.org/10.3389/fcimb.2024.1367938","host_type":""},{"url":"https://hdl.handle.net/1887/3765751","host_type":""}],"fields_of_study":["Antimicrobial Resistance in Staphylococcus","Plant-Microbe Interactions and Immunity","Plant Pathogenic Bacteria Studies","0301 basic medicine","0303 health sciences","03 medical and health sciences"],"mesh_terms":["Animals","Anti-Bacterial Agents","Humans","Microbial Sensitivity Tests","Staphylococcal Infections","Staphylococcus aureus","Zebrafish","Methicillin-Resistant Staphylococcus aureus"],"keywords":["Staphylococcus aureus","Microbiology","Intracellular","Methicillin-resistant Staphylococcus aureus","Lapatinib","Biology","Antibiotics","Intracellular parasite","Drug resistance","Bacteria","Cell biology","Intracellular infection","Zebrafish embryo","Autophagy","Ampk","Host-directed Therapy","Egfr/her Kinase Family","Published Kinase Inhibitor Set (Pkis)","Microbial Sensitivity Tests","Staphylococcal Infections","QR1-502","Anti-Bacterial Agents","Cellular and Infection Microbiology","Humans","Animals","Zebrafish"],"sdg_mappings":[{"sdg_number":3,"sdg_label":"3. 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