{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T18:43:37Z","timestamp":1786128217445,"version":"build-2736575974"},"update-to":[{"DOI":"10.1371\/journal.ppat.1014474","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T00:00:00Z","timestamp":1786060800000}}],"reference-count":55,"publisher":"Public Library of Science (PLoS)","issue":"8","license":[{"start":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T00:00:00Z","timestamp":1785715200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000615","name":"Fight for Sight UK","doi-asserted-by":"publisher","award":["5175\/5176"],"award-info":[{"award-number":["5175\/5176"]}],"id":[{"id":"10.13039\/501100000615","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000268","name":"Biotechnology and Biological Sciences Research Council","doi-asserted-by":"publisher","award":["BB\/X002780\/1"],"award-info":[{"award-number":["BB\/X002780\/1"]}],"id":[{"id":"10.13039\/501100000268","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plospathogens.org"],"crossmark-restriction":false},"short-container-title":["PLoS Pathog"],"abstract":"<jats:p>\n                    Microbial keratitis caused by Exotoxin U (ExoU)-producing strains of\n                    <jats:italic>Pseudomonas aeruginosa<\/jats:italic>\n                    is associated with poor clinical outcomes and reduced responsiveness to antimicrobial therapy. ExoU, a phospholipase, is secreted directly into host cells, causing their lysis. A screen of 3,034 FDA-approved compounds identified zinc pyrithione (Zp), bismuth subcitrate (Bis), and polymyxin B (Pol) as lead inhibitors of ExoU selectively inhibiting it without affecting human PLA2s or bacterial viability. The compounds have distinct inhibitory mechanisms: Zp disrupted ExoU oligomerization and protein stability; Bis impaired phosphatidylinositol 4,5-bisphosphate-dependent membrane association; Pol directly inhibited catalysis via its lipid-peptide architecture. Compound combinations enhanced ExoU inhibition\n                    <jats:italic>in vitro<\/jats:italic>\n                    to nanomolar concentrations. In mammalian cells, Bis and Pol promoted lysosomal trafficking and degradation of ExoU. A high content screen of 52\n                    <jats:italic>P. aeruginosa<\/jats:italic>\n                    keratitis isolates demonstrated the broad efficacy of these inhibitors in\n                    <jats:italic>exoU<\/jats:italic>\n                    \u207a strains. Therapeutic efficacy was evaluated in\n                    <jats:italic>ex vivo<\/jats:italic>\n                    porcine corneas,\n                    <jats:italic>Galleria mellonella<\/jats:italic>\n                    , and\n                    <jats:italic>in vivo<\/jats:italic>\n                    mouse keratitis models. Topical delivery of ExoU inhibitors, particularly in combination, significantly reduced corneal opacity, ulceration, and stromal damage in porcine corneas without affecting bacterial load. In\n                    <jats:italic>Galleria<\/jats:italic>\n                    , compound combinations significantly maintained larval health, improved larval survival and delayed mortality. In a mouse eye infection model, combinatorial treatment reduced disease severity and preserved tissue viability without altering bacterial burden. These findings validate ExoU as a druggable virulence factor and support the repurposing of these compounds as an antivirulence strategy for the treatment of\n                    <jats:italic>P. aeruginosa<\/jats:italic>\n                    infections in human beings and in veterinary medicine.\n                  <\/jats:p>","DOI":"10.1371\/journal.ppat.1014474","type":"journal-article","created":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T17:39:56Z","timestamp":1785778796000},"page":"e1014474","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["Topical formulation of repurposed FDA-approved compounds inhibits Pseudomonas aeruginosa ExoU and improves corneal infection outcomes"],"prefix":"10.1371","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1021-6740","authenticated-orcid":true,"given":"Daniel M.","family":"Foulkes","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David G.","family":"Fernig","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keri","family":"McLean","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie","family":"Held","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John A.","family":"Harris","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joanne L.","family":"Fothergill","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valerie","family":"Price","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dominic P.","family":"Byrne","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriela","family":"Czanner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Connie","family":"Tam","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen B.","family":"Kaye","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2026,8,3]]},"reference":[{"key":"ppat.1014474.ref001","doi-asserted-by":"crossref","first-page":"101031","DOI":"10.1016\/j.preteyeres.2021.101031","article-title":"Bacterial keratitis: identifying the areas of clinical uncertainty","volume":"89","author":"S Tuft","year":"2022","journal-title":"Prog Retin Eye Res"},{"issue":"2","key":"ppat.1014474.ref002","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1016\/j.jinf.2016.11.008","article-title":"Intensive care unit-acquired pneumonia due to Pseudomonas aeruginosa with and without multidrug resistance","volume":"74","author":"L Fern\u00e1ndez-Barat","year":"2017","journal-title":"J Infect"},{"issue":"2","key":"ppat.1014474.ref003","doi-asserted-by":"crossref","first-page":"266","DOI":"10.1016\/j.jinf.2020.05.046","article-title":"Co-infections in people with COVID-19: a systematic review and meta-analysis","volume":"81","author":"L Lansbury","year":"2020","journal-title":"J Infect"},{"issue":"9","key":"ppat.1014474.ref004","doi-asserted-by":"crossref","first-page":"1033","DOI":"10.1016\/S1473-3099(25)00118-5","article-title":"The WHO Bacterial Priority Pathogens List 2024: a prioritisation study to guide research, development, and public health strategies against antimicrobial resistance. 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