{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T19:40:15Z","timestamp":1784835615543,"version":"3.55.0"},"posted":{"date-parts":[[2025,1,29]]},"group-title":"Microbiology","reference-count":0,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,1,29]],"date-time":"2025-01-29T00:00:00Z","timestamp":1738108800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,1,29]]},"abstract":"<jats:p>The rise of antibiotic-resistant bacterial pathogens poses a critical global health challenge, necessitating innovative therapeutic approaches. This study explores host-targeted therapies (HTTs) by focusing on deubiquitinating enzymes (DUBs), essential modulators of the ubiquitin-proteasome system (UPS) that regulate host-pathogen interactions during many bacterial infections. Using Salmonella-infected macrophages as a model, we identified UPS modulators that enhance bacterial clearance and observed significant changes in DUB expression, particularly USP25, USP46, and Otud7b. The small-molecule DUB inhibitor AZ-1 significantly reduced intracellular bacterial loads in vitro and mitigated early disease severity in a murine model by decreasing fecal bacterial loads and preserving host weight. However, AZ-1 alone did not achieve complete clearance of Salmonella and required combination with extracellular-targeting antibiotics for optimal efficacy. Notably, AZ-1 demonstrated broad-spectrum activity against multidrug-resistant pathogens, including Pseudomonas aeruginosa, Klebsiella pneumoniae, and Acinetobacter baumannii. Transcriptomic analyses revealed infection-induced DUB regulation and highlighted pathways modulating immune responses, including TNF-\u03b1 secretion. These findings highlight the potential of targeting the UPS as a host-directed antimicrobial strategy and provide a foundation for developing innovative therapies to combat antimicrobial resistance.<\/jats:p>","DOI":"10.1101\/2025.01.27.635188","type":"posted-content","created":{"date-parts":[[2025,1,29]],"date-time":"2025-01-29T17:35:12Z","timestamp":1738172112000},"source":"Crossref","is-referenced-by-count":3,"title":["Targeting deubiquitinating enzymes (DUBs) and ubiquitin pathway modulators to enhance host defense against bacterial infections"],"prefix":"10.64898","author":[{"given":"John","family":"Santelices","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander C","family":"Schultz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alyssa","family":"Walker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-2499-7036","authenticated-orcid":false,"given":"Nicole","family":"Adams","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deyaneira","family":"Tirado","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hailey","family":"Barker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4944-9146","authenticated-orcid":false,"given":"Aria","family":"Eshraghi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7491-5292","authenticated-orcid":false,"given":"Daniel M.","family":"Czyz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0459-7716","authenticated-orcid":false,"given":"Mariola J","family":"Ferraro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1101\/2025.01.27.635188","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T07:56:57Z","timestamp":1768463817000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.1101\/2025.01.27.635188"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,1,29]]},"references-count":0,"URL":"https:\/\/doi.org\/10.1101\/2025.01.27.635188","relation":{"is-preprint-of":[{"id-type":"doi","id":"10.1128\/mbio.00312-25","asserted-by":"subject"}]},"subject":[],"published":{"date-parts":[[2025,1,29]]},"subtype":"preprint"}}