{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T21:33:51Z","timestamp":1789594431425,"version":"build-2803163510"},"reference-count":43,"publisher":"American Society for Microbiology","issue":"4","license":[{"start":{"date-parts":[[2017,4,1]],"date-time":"2017-04-01T00:00:00Z","timestamp":1491004800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"funder":[{"name":"CHU Grenoble-Alpes"},{"DOI":"10.13039\/100005445","name":"NSF | BFA | Division of Grants and Agreements","doi-asserted-by":"publisher","award":["07C0301"],"award-info":[{"award-number":["07C0301"]}],"id":[{"id":"10.13039\/100005445","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Antimicrob Agents Chemother"],"published-print":{"date-parts":[[2017,4]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Fluoroquinolone (FQ) resistance is a major health concern in the treatment of tularemia. Because DNA gyrase has been described as the main target of these compounds, our aim was to clarify the contributions of both GyrA and GyrB mutations found in\n                    <jats:named-content content-type=\"genus-species\">Francisella novicida<\/jats:named-content>\n                    clones highly resistant to FQs. Wild-type and mutated GyrA and GyrB subunits were overexpressed so that the\n                    <jats:italic>in vitro<\/jats:italic>\n                    FQ sensitivity of functional reconstituted complexes could be evaluated. The data obtained were compared to the MICs of FQs against bacterial clones harboring the same mutations and were further validated through complementation experiments and structural modeling. Whole-genome sequencing of highly FQ-resistant lineages was also done. Supercoiling and DNA cleavage assays demonstrated that GyrA D87 is a hot spot FQ resistance target in\n                    <jats:named-content content-type=\"genus-species\">F. novicida<\/jats:named-content>\n                    and pointed out the role of the GyrA P43H substitution in resistance acquisition. An unusual feature of FQ resistance acquisition in\n                    <jats:named-content content-type=\"genus-species\">F. novicida<\/jats:named-content>\n                    is that the first-step mutation occurs in GyrB, with direct or indirect consequences for FQ sensitivity. Insertion of P466 into GyrB leads to a 50% inhibitory concentration (IC\n                    <jats:sub>50<\/jats:sub>\n                    ) comparable to that observed for a mutant gyrase carrying the GyrA D87Y substitution, while the D487E-\u0394K488 mutation, while not active on its own, contributes to the high level of resistance that occurs following acquisition of the GyrA D87G substitution in double GyrA\/GyrB mutants. The involvement of other putative targets is discussed, including that of a ParE mutation that was found to arise in the very late stage of antibiotic exposure. This study provides the first characterization of the molecular mechanisms responsible for FQ resistance in\n                    <jats:named-content content-type=\"genus-species\">Francisella<\/jats:named-content>\n                    .\n                  <\/jats:p>","DOI":"10.1128\/aac.02277-16","type":"journal-article","created":{"date-parts":[[2017,2,6]],"date-time":"2017-02-06T20:50:11Z","timestamp":1486414211000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":15,"title":["Functional Characterization of the DNA Gyrases in Fluoroquinolone-Resistant Mutants of Francisella novicida"],"prefix":"10.1128","volume":"61","author":[{"given":"Yvan","family":"Caspar","sequence":"first","affiliation":[{"name":"TIMC-IMAG UMR 5525, UGA CNRS, Grenoble, France"},{"name":"Centre Hospitalier Universitaire Grenoble-Alpes, Centre National de R\u00e9f\u00e9rence des Francisella, CS 10217, Grenoble, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claire","family":"Siebert","sequence":"additional","affiliation":[{"name":"TIMC-IMAG UMR 5525, UGA CNRS, Grenoble, France"},{"name":"Centre Hospitalier Universitaire Grenoble-Alpes, Centre National de R\u00e9f\u00e9rence des Francisella, CS 10217, Grenoble, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vivien","family":"Sutera","sequence":"additional","affiliation":[{"name":"Centre Hospitalier Universitaire Grenoble-Alpes, Centre National de R\u00e9f\u00e9rence des Francisella, CS 10217, Grenoble, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Corinne","family":"Villers","sequence":"additional","affiliation":[{"name":"TIMC-IMAG UMR 5525, UGA CNRS, Grenoble, France"},{"name":"Universit\u00e9 de Caen Normandie, EA4655 U2RM (Unit\u00e9 de Recherche Risques Microbiens), Caen, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandra","family":"Aubry","sequence":"additional","affiliation":[{"name":"Sorbonne Universit\u00e9, UPMC Universit\u00e9 Paris 06, CR7, Centre d'Immunologie et des Maladies Infectieuses, Team 13, INSERM U1135, Paris, France"},{"name":"AP-HP, H\u00f4pital Piti\u00e9-Salp\u00eatri\u00e8re, Centre National de R\u00e9f\u00e9rence des Mycobact\u00e9ries et de la R\u00e9sistance des Mycobact\u00e9ries aux Antituberculeux, Bact\u00e9riologie-Hygi\u00e8ne, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudine","family":"Mayer","sequence":"additional","affiliation":[{"name":"Institut Pasteur, Paris, France"},{"name":"CNRS, UMR 3528, Paris, France"},{"name":"Universit\u00e9 Paris Diderot, Sorbonne Paris Cit\u00e9, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Max","family":"Maurin","sequence":"additional","affiliation":[{"name":"TIMC-IMAG UMR 5525, UGA CNRS, Grenoble, France"},{"name":"Centre Hospitalier Universitaire Grenoble-Alpes, Centre National de R\u00e9f\u00e9rence des Francisella, CS 10217, Grenoble, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patricia","family":"Renesto","sequence":"additional","affiliation":[{"name":"TIMC-IMAG UMR 5525, UGA CNRS, Grenoble, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1196\/annals.1409.009"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrmicro1045"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1586\/14787210.2015.986463"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1196\/annals.1409.017"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(15)00355-2"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.3389\/fcimb.2014.00040"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1751-7915.2008.00063.x"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0959-440X(98)80006-7"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1101\/gr.071266.107"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.mcp.2010.01.003"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/dkt321"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.73.11.3872"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1021\/bi5000564"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1111\/nyas.12830"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tim.2014.04.007"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01584-07"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng.1034"},{"key":"e_1_3_3_19_2","first-page":"265","article-title":"Bacterial evolution and the cost of antibiotic resistance","volume":"1","author":"Lenski RE","year":"1998","unstructured":"Lenski RE . 1998. Bacterial evolution and the cost of antibiotic resistance. Int Microbiol1:265\u2013270.","journal-title":"Int Microbiol"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0163458"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a010314"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00707-11"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0084409"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01380-07"},{"key":"e_1_3_3_25_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.45.8.2378-2380.2001"},{"key":"e_1_3_3_26_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(02)00369-9"},{"key":"e_1_3_3_27_2","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/civ790"},{"key":"e_1_3_3_28_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M113.529164"},{"key":"e_1_3_3_29_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijid.2015.01.014"},{"key":"e_1_3_3_30_2","doi-asserted-by":"publisher","DOI":"10.1128\/CMR.00040-09"},{"key":"e_1_3_3_31_2","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.00430-08"},{"key":"e_1_3_3_32_2","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2011.00029"},{"key":"e_1_3_3_33_2","doi-asserted-by":"publisher","DOI":"10.1099\/mic.0.051599-0"},{"key":"e_1_3_3_34_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0020884"},{"key":"e_1_3_3_35_2","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2180-10-123"},{"key":"e_1_3_3_36_2","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.00702-09"},{"key":"e_1_3_3_37_2","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.00503-10"},{"key":"e_1_3_3_38_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.48.4.1281-1288.2004"},{"key":"e_1_3_3_39_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0012245"},{"key":"e_1_3_3_40_2","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2015.053"},{"key":"e_1_3_3_41_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1525047113"},{"key":"e_1_3_3_42_2","doi-asserted-by":"publisher","DOI":"10.1107\/S0907444910007493"},{"key":"e_1_3_3_43_2","doi-asserted-by":"publisher","DOI":"10.1128\/AEM.70.12.7511-7519.2004"},{"key":"e_1_3_3_44_2","doi-asserted-by":"publisher","DOI":"10.1111\/cmi.12227"}],"container-title":["Antimicrobial Agents and Chemotherapy"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/AAC.02277-16","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/AAC.02277-16","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,2,21]],"date-time":"2022-02-21T15:54:28Z","timestamp":1645458868000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.asm.org\/doi\/10.1128\/AAC.02277-16"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,4]]},"references-count":43,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2017,4]]}},"alternative-id":["10.1128\/AAC.02277-16"],"URL":"https:\/\/doi.org\/10.1128\/aac.02277-16","relation":{},"ISSN":["0066-4804","1098-6596"],"issn-type":[{"value":"0066-4804","type":"print"},{"value":"1098-6596","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,4]]},"assertion":[{"value":"2016-10-24","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2017-01-20","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2017-03-24","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e02277-16"}}