{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T18:13:08Z","timestamp":1790187188317,"version":"4.1.0"},"update-to":[{"DOI":"10.1371\/journal.ppat.1014596","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T00:00:00Z","timestamp":1790121600000}}],"reference-count":48,"publisher":"Public Library of Science (PLoS)","issue":"9","license":[{"start":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T00:00:00Z","timestamp":1789516800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.plospathogens.org"],"crossmark-restriction":false},"short-container-title":["PLoS Pathog"],"abstract":"<jats:p>\n                    <jats:italic>Burkholderia pseudomallei (Bp)<\/jats:italic>\n                    and\n                    <jats:italic>Burkholderia mallei (Bm)<\/jats:italic>\n                    are the etiological agents of the fatal diseases melioidosis and glanders, respectively. No licensed vaccine is available to protect against these facultative intracellular bacteria and treatment of infection is difficult, requiring intensive and prolonged antimicrobial therapy with low success rates due to intrinsic resistance of\n                    <jats:italic>Bp<\/jats:italic>\n                    and\n                    <jats:italic>Bm<\/jats:italic>\n                    to most antibiotics. This, combined with concerns regarding their adversarial use as biological warfare agents, emphasize an immediate need to identify novel and effective countermeasures for the organisms. Herein, we developed an\n                    <jats:italic>in vitro<\/jats:italic>\n                    high-content imaging, high-throughput screening platform and tested a\n                    <jats:bold>L<\/jats:bold>\n                    ibrary of\n                    <jats:bold>P<\/jats:bold>\n                    harmacologically\n                    <jats:bold>A<\/jats:bold>\n                    ctive\n                    <jats:bold>C<\/jats:bold>\n                    ompounds (LOPAC) and the Repurposing,\n                    <jats:bold>F<\/jats:bold>\n                    ocused\n                    <jats:bold>R<\/jats:bold>\n                    escue, and\n                    <jats:bold>A<\/jats:bold>\n                    ccelerated\n                    <jats:bold>ME<\/jats:bold>\n                    dchem (ReFRAME) library of small molecules for bioactive compounds protecting against bacterial intracellular replication, which is a key pathogenicity trait of\n                    <jats:italic>Bp<\/jats:italic>\n                    and\n                    <jats:italic>Bm.<\/jats:italic>\n                    We first analyzed confocal microscopy images of\n                    <jats:italic>Burkholderia<\/jats:italic>\n                    -infected monolayers of Vero E6 cells and established a reproducible endpoint readout that quantifies cytopathic effects and the formation of plaques during infection. Following this, we screened ~14,800 small molecules and identified 170 unique structures providing\u2009\u2265 \u200975% inhibition of intracellular replication of\n                    <jats:italic>Bp<\/jats:italic>\n                    and\n                    <jats:italic>Bm<\/jats:italic>\n                    with EC\n                    <jats:sub>50<\/jats:sub>\n                    values ranging from 1 pM to 9.99 \u00b5M. Of these hits, 23 were found to disrupt the intracellular replication of both organisms including 8 compounds targeting dihydrofolate reductase, 3 tetracycline-class antibiotics, an inhibitor of bacterial leucyl-tRNA synthetase (epetraborole), and 2 host-directed compounds targeting receptors on the surface of mammalian cells. Selected compounds were evaluated\n                    <jats:italic>in vivo<\/jats:italic>\n                    using a BALB\/c mouse model of aerosol infection and we discovered that daily treatment with epetraborole (20 mg\/kg) and the fluoroquinolone levofloxacin (5 mg\/kg) completely protected mice against exposure to lethal doses of\n                    <jats:italic>Bm<\/jats:italic>\n                    and\n                    <jats:italic>Bp<\/jats:italic>\n                    , reducing bacterial burdens in the lungs and spleen to undetectable levels in all animals by day 14 post-challenge.\n                  <\/jats:p>","DOI":"10.1371\/journal.ppat.1014596","type":"journal-article","created":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T17:53:01Z","timestamp":1789581181000},"page":"e1014596","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["Discovery of repurposed drugs that disrupt intracellular replication of Burkholderia pseudomallei and Burkholderia mallei and protect against lethal aerosol infection"],"prefix":"10.1371","volume":"22","author":[{"given":"Nichole","family":"Orr-Burks","sequence":"first","affiliation":[{"name":"College of Veterinary Medicine, University of Georgia","place":["Athens, Georgia, United States of America"],"department":["Department of Biomedical Sciences"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah R.","family":"Hosking","sequence":"additional","affiliation":[{"name":"College of Veterinary Medicine, University of Georgia","place":["Athens, Georgia, United States of America"],"department":["Department of Infectious Diseases"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven P.","family":"Maher","sequence":"additional","affiliation":[{"name":"University of Georgia","place":["Athens, Georgia, United States of America"],"department":["Center for Tropical and Emerging Global Diseases"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dennis E.","family":"Kyle","sequence":"additional","affiliation":[{"name":"College of Veterinary Medicine, University of Georgia","place":["Athens, Georgia, United States of America"],"department":["Department of Infectious Diseases"]},{"name":"University of Georgia","place":["Athens, Georgia, United States of America"],"department":["Center for Tropical and Emerging Global Diseases"]},{"name":"University of Georgia","place":["Athens, Georgia, United States of America"],"department":["Department of Cellular Biology"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Malina A.","family":"Bakowski","sequence":"additional","affiliation":[{"name":"Calibr-Skaggs Institute for Innovative Medicines","place":["La Jolla, California, United States of America"],"department":["Division of Scripps Research"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert J.","family":"Hogan","sequence":"additional","affiliation":[{"name":"College of Veterinary Medicine, University of Georgia","place":["Athens, Georgia, United States of America"],"department":["Department of Biomedical Sciences"]},{"name":"College of Veterinary Medicine, University of Georgia","place":["Athens, Georgia, United States of America"],"department":["Department of Infectious Diseases"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2252-2139","authenticated-orcid":true,"given":"Eric R.","family":"Lafontaine","sequence":"additional","affiliation":[{"name":"College of Veterinary Medicine, University of Georgia","place":["Athens, Georgia, United States of America"],"department":["Department of Biomedical Sciences"]},{"name":"College of Veterinary Medicine, University of Georgia","place":["Athens, Georgia, United States of America"],"department":["Department of Infectious Diseases"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2026,9,16]]},"reference":[{"key":"ppat.1014596.ref001","doi-asserted-by":"crossref","first-page":"15008","DOI":"10.1038\/nmicrobiol.2015.8","article-title":"Predicted global distribution of Burkholderia pseudomallei and burden of melioidosis","volume":"1","author":"D Limmathurotsakul","year":"2016","journal-title":"Nat Microbiol"},{"issue":"25","key":"ppat.1014596.ref002","doi-asserted-by":"crossref","first-page":"2355","DOI":"10.1056\/NEJMoa2306448","article-title":"Locally acquired melioidosis linked to environment - Mississippi, 2020-2023","volume":"389","author":"JK Petras","year":"2023","journal-title":"N Engl J Med"},{"issue":"6","key":"ppat.1014596.ref003","doi-asserted-by":"crossref","first-page":"1081","DOI":"10.4269\/ajtmh.23-0223","article-title":"The expanding global footprint of Burkholderia pseudomallei and Melioidosis","volume":"108","author":"BJ 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