{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T06:08:34Z","timestamp":1789625314113,"version":"build-2803163510"},"reference-count":56,"publisher":"Public Library of Science (PLoS)","issue":"3","license":[{"start":{"date-parts":[[2021,3,25]],"date-time":"2021-03-25T00:00:00Z","timestamp":1616630400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100010418","name":"Defence Science and Technology Laboratory","doi-asserted-by":"publisher","award":["Dstlx-1000060221"],"award-info":[{"award-number":["Dstlx-1000060221"]}],"id":[{"id":"10.13039\/100010418","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>\n                    <jats:italic>Burkholderia pseudomallei<\/jats:italic>\n                    is a soil-dwelling organism present throughout the tropics. It is the causative agent of melioidosis, a disease that is believed to kill 89,000 people per year. It is naturally resistant to many antibiotics, requiring at least two weeks of intravenous treatment with ceftazidime, imipenem or meropenem followed by 6 months of orally delivered co-trimoxazole. This places a large treatment burden on the predominantly middle-income nations where the majority of disease occurs. We have established a high-throughput assay for compounds that could be used as a co-therapy to potentiate the effect of ceftazidime, using the related non-pathogenic bacterium\n                    <jats:italic>Burkholderia thailandensis<\/jats:italic>\n                    as a surrogate. Optimization of the assay gave a Z\u2019 factor of 0.68. We screened a library of 61,250 compounds and identified 29 compounds with a\n                    <jats:italic>p<\/jats:italic>\n                    IC\n                    <jats:sub>50<\/jats:sub>\n                    (-log\n                    <jats:sub>10<\/jats:sub>\n                    (IC\n                    <jats:sub>50<\/jats:sub>\n                    )) greater than five. Detailed investigation allowed us to down select to six \u201cbest in class\u201d compounds, which included the licensed drug chloroxine. Co-treatment of\n                    <jats:italic>B<\/jats:italic>\n                    .\n                    <jats:italic>thailandensis<\/jats:italic>\n                    with ceftazidime and chloroxine reduced culturable cell numbers by two orders of magnitude over 48 hours, compared to treatment with ceftazidime alone. Hit expansion around chloroxine was performed using commercially available compounds. Minor modifications to the structure abolished activity, suggesting that chloroxine likely acts against a specific target. Finally, an initial study demonstrates the utility of chloroxine to act as a co-therapy to potentiate the effect of ceftazidime against\n                    <jats:italic>B<\/jats:italic>\n                    .\n                    <jats:italic>pseudomallei<\/jats:italic>\n                    . This approach successfully identified potential co-therapies for a recalcitrant Gram-negative bacterial species. Our assay could be used more widely to aid in chemotherapy to treat infections caused by these bacteria.\n                  <\/jats:p>","DOI":"10.1371\/journal.pone.0248119","type":"journal-article","created":{"date-parts":[[2021,3,25]],"date-time":"2021-03-25T15:57:32Z","timestamp":1616687852000},"page":"e0248119","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":3,"title":["Drug screening to identify compounds to act as co-therapies for the treatment of Burkholderia species"],"prefix":"10.1371","volume":"16","author":[{"given":"Sam","family":"Barker","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah V.","family":"Harding","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Gray","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark I.","family":"Richards","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helen S.","family":"Atkins","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4073-0505","authenticated-orcid":true,"given":"Nicholas J.","family":"Harmer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2021,3,25]]},"reference":[{"issue":"11","key":"pone.0248119.ref001","doi-asserted-by":"crossref","first-page":"1035","DOI":"10.1056\/NEJMra1204699","article-title":"Melioidosis.","volume":"367","author":"WJ Wiersinga","year":"2012","journal-title":"N Engl J Med"},{"issue":"7586","key":"pone.0248119.ref002","doi-asserted-by":"crossref","first-page":"290","DOI":"10.1038\/529290a","article-title":"Epidemiology: A global picture of melioidosis","volume":"529","author":"BJ Currie","year":"2016","journal-title":"Nature"},{"key":"pone.0248119.ref003","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":"4","key":"pone.0248119.ref004","doi-asserted-by":"crossref","first-page":"272","DOI":"10.1038\/nrmicro1385","article-title":"Melioidosis: insights into the pathogenicity of Burkholderia pseudomallei","volume":"4","author":"WJ Wiersinga","year":"2006","journal-title":"Nat Rev Microbiol"},{"issue":"2","key":"pone.0248119.ref005","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1128\/CMR.18.2.383-416.2005","article-title":"Melioidosis: epidemiology, pathophysiology, and management","volume":"18","author":"AC Cheng","year":"2005","journal-title":"Clin Microbiol 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