{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,10]],"date-time":"2026-07-10T01:15:53Z","timestamp":1783646153071,"version":"3.55.0"},"reference-count":50,"publisher":"American Society for Microbiology","issue":"1","license":[{"start":{"date-parts":[[2024,1,11]],"date-time":"2024-01-11T00:00:00Z","timestamp":1704931200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2024,1,11]],"date-time":"2024-01-11T00:00:00Z","timestamp":1704931200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"funder":[{"name":"MIP Pharma GmbH","award":["n\/a"],"award-info":[{"award-number":["n\/a"]}]}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Microbiol Spectr"],"published-print":{"date-parts":[[2024,1,11]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:p>\n            Nitroxoline (NTX) is an antibiotic approved for the treatment of uncomplicated urinary tract infections (UTIs) caused by Enterobacteriaceae like\n            <jats:italic>Escherichia coli<\/jats:italic>\n            , and it has been on the market for more than 50 years. Despite being in use longer than several other clinically relevant antibiotics, the resistance of clinical isolates against NTX has not evolved significantly. To better understand this observation, we performed a standardized\n            <jats:italic>in vitro<\/jats:italic>\n            evaluation of NTX in comparison to other UTI drugs with a focus on resistance development and especially their consequences. We have managed to generate low-level resistant mutants in\n            <jats:italic>E. coli<\/jats:italic>\n            and\n            <jats:italic>Klebsiella pneumoniae<\/jats:italic>\n            using a long-term exposure setup, and identified mutations in different efflux-related genes and in other pleiotropic regulators as well as the sensor histidine kinase\n            <jats:italic>envZ<\/jats:italic>\n            . Subsequently, mutants were characterized by metabolic and proteomic analyses confirming major effects of NTX resistance on both metabolism and differential protein expression of\n            <jats:italic>E. coli<\/jats:italic>\n            , which ultimately also translates into reduced\n            <jats:italic>in vitro<\/jats:italic>\n            motility and\n            <jats:italic>in vivo<\/jats:italic>\n            virulence of mutant strains as shown in a zebrafish larvae infection model.\n          <\/jats:p>\n          <jats:sec>\n            <jats:title>IMPORTANCE<\/jats:title>\n            <jats:p>\n              Antimicrobial resistance (AMR) poses a global threat and requires the exploration of underestimated treatment options. Nitroxoline, an effective broad-spectrum antibiotic, does not suffer from high resistance rates in the clinics but surprisingly, it is not heavily used yet. Our findings provide compelling evidence that Nitroxoline resistance renders bacteria unable to cause an infection\n              <jats:italic>in vivo<\/jats:italic>\n              , thereby reinvigorating the potential of Nitroxoline in combating AMR.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1128\/spectrum.03079-23","type":"journal-article","created":{"date-parts":[[2023,12,8]],"date-time":"2023-12-08T14:00:17Z","timestamp":1702044017000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":15,"title":["Nitroxoline resistance is associated with significant fitness loss and diminishes\n            <i>in vivo<\/i>\n            virulence of\n            <i>Escherichia coli<\/i>"],"prefix":"10.1128","volume":"12","author":[{"given":"Felix","family":"Deschner","sequence":"first","affiliation":[{"name":"Microbial Natural Products, Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Centre for Infection Research (HZI) and Department of Pharmacy Saarland University , Saarbr\u00fccken, Germany"},{"name":"German Centre for Infection Research (DZIF) , Braunschweig, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timo","family":"Risch","sequence":"additional","affiliation":[{"name":"Microbial Natural Products, Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Centre for Infection Research (HZI) and Department of Pharmacy Saarland University , Saarbr\u00fccken, Germany"},{"name":"German Centre for Infection Research (DZIF) , Braunschweig, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claas","family":"Baier","sequence":"additional","affiliation":[{"name":"Institute for Medical Microbiology and Hospital Epidemiology, Hannover Medical School (MHH) , Hannover, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dirk","family":"Schl\u00fcter","sequence":"additional","affiliation":[{"name":"German Centre for Infection Research (DZIF) , Braunschweig, Germany"},{"name":"Institute for Medical Microbiology and Hospital Epidemiology, Hannover Medical School (MHH) , Hannover, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer","family":"Herrmann","sequence":"additional","affiliation":[{"name":"Microbial Natural Products, Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Centre for Infection Research (HZI) and Department of Pharmacy Saarland University , Saarbr\u00fccken, Germany"},{"name":"German Centre for Infection Research (DZIF) , Braunschweig, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1042-5665","authenticated-orcid":false,"given":"Rolf","family":"M\u00fcller","sequence":"additional","affiliation":[{"name":"Microbial Natural Products, Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Centre for Infection Research (HZI) and Department of Pharmacy Saarland University , Saarbr\u00fccken, Germany"},{"name":"German Centre for Infection Research (DZIF) , Braunschweig, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_4_2_2","unstructured":"World Health Organisation - Regional Committee for Europe . 2011. Sixty-first regional committee for Europe: baku 12\u201315 September 2011: European strategic action plan on antibiotic resistance. Available from: https:\/\/apps.who.int\/iris\/handle\/10665\/335840. Retrieved 8 Mar 2023."},{"key":"e_1_3_4_3_2","unstructured":"World health organization . 2015. Global action plan on antimicrobial resistance. Available from: https:\/\/apps.who.int\/iris\/handle\/10665\/193736. Retrieved 8 Mar 2023."},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(21)02724-0"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.15252\/embr.202256033"},{"key":"e_1_3_4_6_2","unstructured":"Schmiemann GPD Gebhardt K Hummers EPD . 2018. Brennen beim Wasserlassen S3-leitlinie und Anwenderversion der S3-leitlinie Harnwegsinfektionen DEGAM. Published online. Available from: https:\/\/www.mendeley.com\/catalogue\/27984ee0-fd54-38e9-b882-40a3ced909ad\/?utm_source=desktop. Retrieved 28 Mar 2023."},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.03946-14"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.02147-13"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1093\/jacamr\/dlac059"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.2807\/1560-7917.ES.2023.28.19.2200568"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.39.3.707"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1080\/00958972.2012.744972"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1432-1033.1974.tb03597.x"},{"key":"e_1_3_4_14_2","first-page":"600","article-title":"Relation of the chelating property of nitroxoline, the surface hydrophobicity and the inhibition of bacterial adherence","volume":"37","author":"Bourlioux P","year":"1989","unstructured":"Bourlioux P , Karam D , Amgar A , Perdiz M . 1989. Relation of the chelating property of nitroxoline, the surface hydrophobicity and the inhibition of bacterial adherence. Pathol Biol (Paris) 37:600\u2013604.","journal-title":"Pathol Biol (Paris)"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01484-12"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/dkz434"},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.1111\/mmi.12429"},{"key":"e_1_3_4_18_2","unstructured":"EUCAST . 2023. Breakpoint tables for interpretation of MICs and zone diameters. Version 13.0. Available from: https:\/\/www.eucast.org\/clinical_breakpoints. Retrieved 8 Mar 2023."},{"key":"e_1_3_4_19_2","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2164-9-488"},{"key":"e_1_3_4_20_2","doi-asserted-by":"publisher","DOI":"10.1021\/acsinfecdis.8b00108"},{"key":"e_1_3_4_21_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00120-016-0218-y"},{"key":"e_1_3_4_22_2","doi-asserted-by":"publisher","DOI":"10.3390\/antibiotics10060645"},{"key":"e_1_3_4_23_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00120-017-0389-1"},{"key":"e_1_3_4_24_2","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/dkz275"},{"key":"e_1_3_4_25_2","doi-asserted-by":"publisher","DOI":"10.1099\/jmm.0.001014"},{"key":"e_1_3_4_26_2","doi-asserted-by":"publisher","DOI":"10.1128\/aac.02265-21"},{"key":"e_1_3_4_27_2","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/dkac123"},{"key":"e_1_3_4_28_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12879-014-0628-7"},{"key":"e_1_3_4_29_2","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/dky255"},{"key":"e_1_3_4_30_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.04819-14"},{"key":"e_1_3_4_31_2","doi-asserted-by":"publisher","DOI":"10.2147\/IDR.S209255"},{"key":"e_1_3_4_32_2","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/dkac396"},{"key":"e_1_3_4_33_2","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/dkn222"},{"key":"e_1_3_4_34_2","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/dkm167"},{"key":"e_1_3_4_35_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-020-67820-x"},{"key":"e_1_3_4_36_2","doi-asserted-by":"publisher","DOI":"10.1128\/jb.143.3.1374-1383.1980"},{"key":"e_1_3_4_37_2","doi-asserted-by":"publisher","DOI":"10.1016\/0022-2836(81)90364-8"},{"key":"e_1_3_4_38_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M602112200"},{"key":"e_1_3_4_39_2","doi-asserted-by":"publisher","DOI":"10.1128\/jb.131.2.623-630.1977"},{"key":"e_1_3_4_40_2","doi-asserted-by":"publisher","DOI":"10.3390\/antibiotics11081105"},{"key":"e_1_3_4_41_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01441-10"},{"key":"e_1_3_4_42_2","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2019.00953"},{"key":"e_1_3_4_43_2","doi-asserted-by":"publisher","DOI":"10.1080\/21688370.2021.2013695"},{"key":"e_1_3_4_44_2","doi-asserted-by":"publisher","DOI":"10.1128\/jb.177.16.4696-4702.1995"},{"key":"e_1_3_4_45_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2958.2011.07917.x"},{"key":"e_1_3_4_46_2","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2022.1032969"},{"key":"e_1_3_4_47_2","doi-asserted-by":"publisher","DOI":"10.1007\/BF02818714"},{"key":"e_1_3_4_48_2","doi-asserted-by":"publisher","DOI":"10.1038\/srep16149"},{"key":"e_1_3_4_49_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00253-015-6946-x"},{"key":"e_1_3_4_50_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.micpath.2021.105198"},{"key":"e_1_3_4_51_2","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jproteome.0c00668"}],"container-title":["Microbiology Spectrum"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/spectrum.03079-23","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/spectrum.03079-23","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,1,11]],"date-time":"2024-01-11T14:10:54Z","timestamp":1704982254000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.asm.org\/doi\/10.1128\/spectrum.03079-23"}},"subtitle":[],"editor":[{"given":"Mark William","family":"Pandori","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2024,1,11]]},"references-count":50,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2024,1,11]]}},"alternative-id":["10.1128\/spectrum.03079-23"],"URL":"https:\/\/doi.org\/10.1128\/spectrum.03079-23","relation":{},"ISSN":["2165-0497"],"issn-type":[{"value":"2165-0497","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,1,11]]},"assertion":[{"value":"2023-08-11","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-11-14","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-12-08","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e03079-23"}}