{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T12:06:48Z","timestamp":1787314008805,"version":"build-2736575974"},"reference-count":29,"publisher":"Oxford University Press (OUP)","issue":"8","license":[{"start":{"date-parts":[[2025,7,1]],"date-time":"2025-07-01T00:00:00Z","timestamp":1751328000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,8,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background and objectives<\/jats:title>\n                    <jats:p>Methicillin-resistant Staphylococcus aureus (MRSA) is a principal contributor to mortality and morbidity attributable to antimicrobial resistance. Many MRSA strains are able to invade host cells, thereby further evading antibiotic treatment. Previously, indolocarbazole GW296115X was identified as a hit compound with host-directed activity against intracellular MRSA. This study evaluates the efficacy and selectivity of indolocarbazoles as potential host-directed therapy against intracellular MRSA. Furthermore, we assessed the interaction between indolocarbazoles and standard-of-care antibiotics.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Bioluminescent luxBADCE-expressing MRSA was used to evaluate antimicrobial activity in planktonic cultures and HeLa cell intracellular infection models. Drug safety was assessed through lactate dehydrogenase (LDH) release and WST-1 cytotoxicity assays. The interaction between selected indolocarbazoles in combination with vancomycin or daptomycin was determined based on the Bliss independence model.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Indolocarbazoles GW296115X, staurosporine aglycone, CDK4 inhibitor and SB-218078 showed activity against intracellular MRSA with SB-218078 demonstrating the best potency. None of the effective compounds impaired host cell viability, although host cell metabolic activity was affected to various extents. Combining SB-218078 or GW296115X with vancomycin or daptomycin synergistically eradicated both intracellular and extracellular MRSA.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Indolocarbazoles, particularly GW296115X and SB-218078, enhance standard antibiotic efficacy against invasive MRSA and offer potential for host-directed therapy.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/jac\/dkaf198","type":"journal-article","created":{"date-parts":[[2025,6,6]],"date-time":"2025-06-06T07:51:15Z","timestamp":1749196275000},"page":"2257-2268","source":"Crossref","is-referenced-by-count":2,"title":["Indolocarbazoles as host-directed therapeutics against intracellular infections by methicillin-resistant\n                    <i>Staphylococcus aureus<\/i>"],"prefix":"10.1093","volume":"80","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6247-9705","authenticated-orcid":false,"given":"Robin H G A","family":"van den Biggelaar","sequence":"first","affiliation":[{"name":"Leiden University Center for Infectious Diseases, Leiden University Medical Center , Leiden ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Erdkamp","sequence":"additional","affiliation":[{"name":"Leiden University Center for Infectious Diseases, Leiden University Medical Center , Leiden ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adri\u00ebtte W","family":"de Visser","sequence":"additional","affiliation":[{"name":"Leiden University Center for Infectious Diseases, Leiden University Medical Center , Leiden ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susan J F","family":"van den Eeden","sequence":"additional","affiliation":[{"name":"Leiden University Center for Infectious Diseases, Leiden University Medical Center , Leiden ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anno","family":"Saris","sequence":"additional","affiliation":[{"name":"Leiden University Center for Infectious Diseases, Leiden University Medical Center , Leiden ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2025,7,1]]},"reference":[{"key":"2025080100171922000_dkaf198-B1","doi-asserted-by":"publisher","first-page":"629","DOI":"10.1016\/S0140-6736(21)02724-0","article-title":"Global burden of bacterial antimicrobial resistance in 2019: a systematic 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