{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T17:59:26Z","timestamp":1792519166381,"version":"4.5.0"},"reference-count":58,"publisher":"American Society for Microbiology","issue":"5","license":[{"start":{"date-parts":[[2020,9,15]],"date-time":"2020-09-15T00:00:00Z","timestamp":1600128000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2020,10,27]],"date-time":"2020-10-27T00:00:00Z","timestamp":1603756800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"funder":[{"DOI":"10.13039\/501100001505","name":"Manatu Hauora | Health Research Council of New Zealand","doi-asserted-by":"publisher","award":["18-532"],"award-info":[{"award-number":["18-532"]}],"id":[{"id":"10.13039\/501100001505","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000038","name":"Gouvernement du Canada | Natural Sciences and Engineering Research Council of Canada","doi-asserted-by":"publisher","award":["RGPIN 2017-04909"],"award-info":[{"award-number":["RGPIN 2017-04909"]}],"id":[{"id":"10.13039\/501100000038","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000024","name":"Gouvernement du Canada | Canadian Institutes of Health Research","doi-asserted-by":"publisher","award":["FDN-154287"],"award-info":[{"award-number":["FDN-154287"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100009193","name":"Royal Society of New Zealand | Marsden Fund","doi-asserted-by":"publisher","award":["VUW1502"],"award-info":[{"award-number":["VUW1502"]}],"id":[{"id":"10.13039\/501100009193","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["mBio"],"published-print":{"date-parts":[[2020,10,27]]},"abstract":"<jats:p>\n                    There is a critical need for more-effective treatments to combat multidrug-resistant Gram-negative infections. Combination therapies are a promising strategy, especially when these enable existing clinical drugs to be repurposed as antibiotics. We examined the mechanisms of action and basis of innate Gram-negative resistance for the anthelmintic drug niclosamide and subsequently exploited this information to demonstrate that niclosamide and analogs kill Gram-negative bacteria when combined with antibiotics that inhibit drug efflux or permeabilize membranes. We confirm the synergistic potential of niclosamide\n                    <jats:italic>in vitro<\/jats:italic>\n                    against a diverse range of recalcitrant Gram-negative clinical isolates and\n                    <jats:italic>in vivo<\/jats:italic>\n                    in a mouse abscess model. We also demonstrate that nitroreductases can confer resistance to niclosamide but show that evolution of these enzymes for enhanced niclosamide resistance confers a collateral sensitivity to other clinical antibiotics. Our results highlight how detailed mechanistic understanding can accelerate the evaluation and implementation of new combination therapies.\n                  <\/jats:p>","DOI":"10.1128\/mbio.02068-20","type":"journal-article","created":{"date-parts":[[2020,9,14]],"date-time":"2020-09-14T10:36:30Z","timestamp":1600079790000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":47,"title":["Mechanistic Understanding Enables the Rational Design of Salicylanilide Combination Therapies for Gram-Negative Infections"],"prefix":"10.1128","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6690-0480","authenticated-orcid":false,"given":"Janine N.","family":"Copp","sequence":"first","affiliation":[{"name":"School of Biological Sciences, Victoria University of Wellington, Wellington, New Zealand"},{"name":"Michael Smith Laboratories, University of British Columbia, Vancouver, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5750-7505","authenticated-orcid":false,"given":"Daniel","family":"Pletzer","sequence":"additional","affiliation":[{"name":"Center for Microbial Diseases and Immunity Research, Department of Microbiology and Immunology, University of British Columbia, Vancouver, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alistair S.","family":"Brown","sequence":"additional","affiliation":[{"name":"School of Biological Sciences, Victoria University of Wellington, Wellington, New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joris","family":"Van der Heijden","sequence":"additional","affiliation":[{"name":"Michael Smith Laboratories, University of British Columbia, Vancouver, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charlotte M.","family":"Miton","sequence":"additional","affiliation":[{"name":"Michael Smith Laboratories, University of British Columbia, Vancouver, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca J.","family":"Edgar","sequence":"additional","affiliation":[{"name":"School of Biological Sciences, Victoria University of Wellington, Wellington, New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michelle H.","family":"Rich","sequence":"additional","affiliation":[{"name":"School of Biological Sciences, Victoria University of Wellington, Wellington, New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rory F.","family":"Little","sequence":"additional","affiliation":[{"name":"School of Biological Sciences, Victoria University of Wellington, Wellington, New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elsie M.","family":"Williams","sequence":"additional","affiliation":[{"name":"School of Biological Sciences, Victoria University of Wellington, Wellington, New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5989-8503","authenticated-orcid":false,"given":"Robert E. W.","family":"Hancock","sequence":"additional","affiliation":[{"name":"Center for Microbial Diseases and Immunity Research, Department of Microbiology and Immunology, University of British Columbia, Vancouver, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nobuhiko","family":"Tokuriki","sequence":"additional","affiliation":[{"name":"Michael Smith Laboratories, University of British Columbia, Vancouver, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6188-9902","authenticated-orcid":false,"given":"David F.","family":"Ackerley","sequence":"additional","affiliation":[{"name":"School of Biological Sciences, Victoria University of Wellington, Wellington, New Zealand"},{"name":"Centre for Biodiscovery, Victoria University of Wellington, Wellington, New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","volume-title":"Global priority list of antibiotic-resistant bacteria to guide research, discovery, and development of new antibiotics","author":"World Health Organization","year":"2017","unstructured":"World Health Organization. 2017. Global priority list of antibiotic-resistant bacteria to guide research, discovery, and development of new antibiotics. WHO, Geneva, Switzerland."},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41579-018-0141-x"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1606301113"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng1755"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.3390\/molecules16129819"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1007\/978-3-642-28951-4_6"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.05996-11"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1002\/prp2.149"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2019.04.002"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-03447-x"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijantimicag.2007.02.019"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/dkm071"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1038\/nchembio.559"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.2174\/0929867325666180706101404"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1038\/nmicrobiol.2017.28"},{"key":"e_1_3_2_17_2","first-page":"663","article-title":"Worm cure without tears. The effect of niclosamide on Taeniasis saginata in man","volume":"182","author":"Ditzel J","year":"1967","unstructured":"Ditzel J, Schwartz M. 1967. Worm cure without tears. The effect of niclosamide on Taeniasis saginata in man. J Intern Med 182:663\u2013664.","journal-title":"J Intern Med"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cellsig.2017.04.001"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1038\/2211016a0"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1002\/cmdc.201800100"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.48.7.2693-2696.2004"},{"key":"e_1_3_2_22_2","doi-asserted-by":"crossref","unstructured":"Jeon S Ko M Lee J Choi I Byun SY Park S Shum D Kim S. 2020. Identification of antiviral drug candidates against SARS-CoV-2 from FDA-approved drugs. bioRxiv doi:10.1101\/2020.03.20.999730.","DOI":"10.1101\/2020.03.20.999730"},{"key":"e_1_3_2_23_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1002976"},{"key":"e_1_3_2_24_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0124595"},{"key":"e_1_3_2_25_2","doi-asserted-by":"publisher","DOI":"10.1038\/srep33642"},{"key":"e_1_3_2_26_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-018-22037-x"},{"key":"e_1_3_2_27_2","doi-asserted-by":"publisher","DOI":"10.1016\/0163-7258(82)90064-X"},{"key":"e_1_3_2_28_2","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.7113"},{"key":"e_1_3_2_29_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmc.2015.07.001"},{"key":"e_1_3_2_30_2","doi-asserted-by":"publisher","DOI":"10.1021\/acs.molpharmaceut.5b00098"},{"key":"e_1_3_2_31_2","doi-asserted-by":"publisher","DOI":"10.3389\/fcimb.2018.00348"},{"key":"e_1_3_2_32_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.02574-18"},{"key":"e_1_3_2_33_2","unstructured":"Ackerley DF Copp JN. 2017. Antibacterial compositions. Patent WO2016080846A1."},{"key":"e_1_3_2_34_2","doi-asserted-by":"publisher","DOI":"10.1128\/mBio.00140-17"},{"key":"e_1_3_2_35_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0902400106"},{"key":"e_1_3_2_36_2","doi-asserted-by":"publisher","DOI":"10.1111\/bph.13571"},{"key":"e_1_3_2_37_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1706849114"},{"key":"e_1_3_2_38_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M112.359638"},{"key":"e_1_3_2_39_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcp.2009.10.008"},{"key":"e_1_3_2_40_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00216-014-8171-3"},{"key":"e_1_3_2_41_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.csbj.2015.09.001"},{"key":"e_1_3_2_42_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrmicro2474"},{"key":"e_1_3_2_43_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1414569112"},{"key":"e_1_3_2_44_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0060666"},{"key":"e_1_3_2_45_2","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2015.00587"},{"key":"e_1_3_2_46_2","doi-asserted-by":"publisher","DOI":"10.1038\/nchembio.1361"},{"key":"e_1_3_2_47_2","doi-asserted-by":"publisher","DOI":"10.4155\/fmc-2016-0091"},{"key":"e_1_3_2_48_2","unstructured":"Delavenne EFA Simon DJJ Sommer MOA Toft-Kehler RV Aps A. 2016. Antibacterial use of halogenated salicylanilides. Patent WO2016038035A1."},{"key":"e_1_3_2_49_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.chembiol.2013.07.006"},{"key":"e_1_3_2_50_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1521988112"},{"key":"e_1_3_2_51_2","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2958.1998.00806.x"},{"key":"e_1_3_2_52_2","doi-asserted-by":"publisher","DOI":"10.1038\/msb4100050"},{"key":"e_1_3_2_53_2","doi-asserted-by":"publisher","DOI":"10.1093\/protein\/gzu025"},{"key":"e_1_3_2_54_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1007084"},{"key":"e_1_3_2_55_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00935-19"},{"key":"e_1_3_2_56_2","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2007.521"},{"key":"e_1_3_2_57_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.chembiol.2017.02.005"},{"key":"e_1_3_2_58_2","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btx162"},{"key":"e_1_3_2_59_2","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/dkq169"}],"container-title":["mBio"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/mBio.02068-20","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/mBio.02068-20","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,3,7]],"date-time":"2022-03-07T22:06:49Z","timestamp":1646690809000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.asm.org\/doi\/10.1128\/mBio.02068-20"}},"subtitle":[],"editor":[{"given":"Paul S.","family":"Hoffman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]},{"given":"Nina R.","family":"Salama","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2020,10,27]]},"references-count":58,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2020,10,27]]}},"alternative-id":["10.1128\/mBio.02068-20"],"URL":"https:\/\/doi.org\/10.1128\/mbio.02068-20","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2020.04.23.058875","asserted-by":"object"}]},"ISSN":["2161-2129","2150-7511"],"issn-type":[{"value":"2161-2129","type":"print"},{"value":"2150-7511","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,10,27]]},"assertion":[{"value":"2020-07-27","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2020-08-06","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2020-09-15","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e02068-20"}}