{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,15]],"date-time":"2026-03-15T05:39:07Z","timestamp":1773553147503,"version":"3.50.1"},"reference-count":5,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2023,8,4]],"date-time":"2023-08-04T00:00:00Z","timestamp":1691107200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["analyticalsciencejournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Drug Development Research"],"published-print":{"date-parts":[[2023,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p><jats:italic>Staphylococcus aureus<\/jats:italic> is the leading cause of skin and soft tissue infections. With the emergence of antibiotic\u2010resistant bacteria, there is an unmet clinical need to develop immune\u2010based therapies to treat skin infections. Previously, we have shown pan\u2010caspase inhibition as a potential host\u2010directed immunotherapy against community\u2010acquired methicillin\u2010resistant <jats:italic>S aureus<\/jats:italic> (CA\u2010MRSA) and other bacterial skin infections. Here, we evaluated the role of irreversible pan\u2010caspase inhibitor emricasan as a monotherapy and an adjunctive with a standard\u2010of\u2010care antibiotic, doxycycline, as potential host\u2010directed immunotherapies against <jats:italic>S. aureus<\/jats:italic> skin infections in vivo. We used the established CA\u2010MRSA strain USA300 on the dorsum of WT C57BL\/6J mice and monitored lesion size and bacterial burden noninvasively, and longitudinally over 14 days with in vivo bioluminescence imaging (BLI). Mice in four groups placebo (0.5% carboxymethyl cellulose [CMC] solution), placebo plus doxycycline (100\u2009mg\/kg), emricasan (40\u2009mg\/kg) plus doxycycline, and emricasan only were treated orally twice daily by oral gavage for 7 days, starting at 4\u2009h after injection of <jats:italic>S aureus<\/jats:italic>. When compared with placebo, all three groups, placebo plus doxycycline, emricasan plus doxycycline, and emricasan treated group, exhibited biological effect, with reduction of both the lesion size (*<jats:italic>p<\/jats:italic>\u2009=\u2009.0277, ****<jats:italic>p<\/jats:italic>\u2009&lt;\u2009.0001, ****<jats:italic>p<\/jats:italic>\u2009&lt;\u2009.0001, respectively) and bacterial burden (***<jats:italic>p<\/jats:italic>\u2009=\u2009.003, ****<jats:italic>p<\/jats:italic>\u2009&lt;\u2009.0001, ****<jats:italic>p<\/jats:italic>\u2009&lt;\u2009.0001, respectively). Importantly, the efficacy of emricasan against <jats:italic>S. aureus<\/jats:italic> was not due to direct antibacterial activity. Collectively, pan\u2010caspase inhibitor emricasan and emricasan plus doxycycline reduced both the lesion size and bacterial burden in vivo, and emricasan is a potential host\u2010directed immunotherapy against MRSA skin infections in a preclinical mouse model.<\/jats:p>","DOI":"10.1002\/ddr.22099","type":"journal-article","created":{"date-parts":[[2023,8,4]],"date-time":"2023-08-04T09:11:52Z","timestamp":1691140312000},"page":"1567-1571","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["An oral caspase inhibitor as monotherapy or with antibiotics eradicates MRSA skin infections in mice"],"prefix":"10.1002","volume":"84","author":[{"given":"Emily","family":"Cahill","sequence":"first","affiliation":[{"name":"Department of Dermatology Johns Hopkins University School of Medicine Baltimore Maryland USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Olusola O.","family":"Oladipo","sequence":"additional","affiliation":[{"name":"Department of Dermatology Johns Hopkins University School of Medicine Baltimore Maryland USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dustin","family":"Dikeman","sequence":"additional","affiliation":[{"name":"Department of Dermatology Johns Hopkins University School of Medicine Baltimore Maryland USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Denion","family":"Prifti","sequence":"additional","affiliation":[{"name":"Department of Dermatology Johns Hopkins University School of Medicine Baltimore Maryland USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Steven J.","family":"Mento","sequence":"additional","affiliation":[{"name":"Histogen San Diego California USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lloyd S.","family":"Miller","sequence":"additional","affiliation":[{"name":"Department of Dermatology Johns Hopkins University School of Medicine Baltimore Maryland USA"},{"name":"Janssen Research and Development  Pennsylvania USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3447-1284","authenticated-orcid":false,"given":"Martin P.","family":"Alphonse","sequence":"additional","affiliation":[{"name":"Department of Dermatology Johns Hopkins University School of Medicine Baltimore Maryland USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2023,8,4]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.abe9887"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01003-12"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2019.11.024"},{"key":"e_1_2_9_5_1","unstructured":"Histogen. (2022). Safety and tolerability of emricasan in symptomatic outpatients diagnosed with mild\u2010COVID\u201019. ClinicalTrials.gov ID: NCT04803227.https:\/\/clinicaltrials.gov\/study\/NCT04803227"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1128\/CMR.00181-19"}],"container-title":["Drug Development Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/analyticalsciencejournals.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ddr.22099","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,14]],"date-time":"2025-10-14T06:26:37Z","timestamp":1760423197000},"score":1,"resource":{"primary":{"URL":"https:\/\/analyticalsciencejournals.onlinelibrary.wiley.com\/doi\/10.1002\/ddr.22099"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,8,4]]},"references-count":5,"journal-issue":{"issue":"8","published-print":{"date-parts":[[2023,12]]}},"alternative-id":["10.1002\/ddr.22099"],"URL":"https:\/\/doi.org\/10.1002\/ddr.22099","archive":["Portico"],"relation":{},"ISSN":["0272-4391","1098-2299"],"issn-type":[{"value":"0272-4391","type":"print"},{"value":"1098-2299","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,8,4]]},"assertion":[{"value":"2023-04-20","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-07-27","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-08-04","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}