{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,1]],"date-time":"2026-08-01T21:59:28Z","timestamp":1785621568346,"version":"3.56.0"},"reference-count":37,"publisher":"SAGE Publications","issue":"1","license":[{"start":{"date-parts":[[2018,1,1]],"date-time":"2018-01-01T00:00:00Z","timestamp":1514764800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Microbial Drug Resistance"],"published-print":{"date-parts":[[2018,1]]},"abstract":"<jats:p>\n                    We studied mechanisms of drug resistance development in\n                    <jats:italic toggle=\"yes\">Escherichia coli<\/jats:italic>\n                    strains lacking efflux pump components.\n                    <jats:italic toggle=\"yes\">E. coli<\/jats:italic>\n                    K12 deletion mutants were subjected to increasing concentrations of ciprofloxacin (CIP) to determine the frequency of target gene mutations. We generated a series of mutants that were selected based on their minimum inhibitory concentrations (MICs) to CIP, as well as their corresponding point mutations in target genes. The mutants displayed a number of target modifications and, in particular,\n                    <jats:italic toggle=\"yes\">gyr<\/jats:italic>\n                    A mutations altering codons Ser83Leu, Asp87Gly, and Asp87His as well as a change in\n                    <jats:italic toggle=\"yes\">par<\/jats:italic>\n                    C at 78 (substitution of Gly for Asp). All these mutations were related to drug resistance. When exposed to CIP, mutants lacking efflux pump genes\n                    <jats:italic toggle=\"yes\">acr<\/jats:italic>\n                    A and\n                    <jats:italic toggle=\"yes\">acr<\/jats:italic>\n                    B demonstrated a low level of resistance that was because of point mutations in the target genes. High-level resistance was achieved with a 100- to 500-fold increase in expression of efflux pump genes\n                    <jats:italic toggle=\"yes\">acr<\/jats:italic>\n                    E and\n                    <jats:italic toggle=\"yes\">acr<\/jats:italic>\n                    F that compensated for the loss of AcrA and AcrB, and thus resulted in an obvious increase of CIP MIC. We demonstrate that an intact AcrAB-TolC efflux pump is crucial to the development of bacterial resistance. Its activity is complemented by expression of the alternative AcrEF efflux pump.\n                  <\/jats:p>","DOI":"10.1089\/mdr.2016.0207","type":"journal-article","created":{"date-parts":[[2017,5,18]],"date-time":"2017-05-18T14:28:38Z","timestamp":1495117718000},"page":"18-23","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":32,"title":["Upregulation of AcrEF in Quinolone Resistance Development in\n                    <i>Escherichia coli<\/i>\n                    When AcrAB-TolC Function Is Impaired"],"prefix":"10.1177","volume":"24","author":[{"given":"Chuan-Zhen","family":"Zhang","sequence":"first","affiliation":[{"name":"South China Agricultural University (SCAU)","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Man-Xia","family":"Chang","sequence":"additional","affiliation":[{"name":"South China Agricultural University (SCAU)","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Yang","sequence":"additional","affiliation":[{"name":"South China Agricultural University (SCAU)","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan-Yan","family":"Liu","sequence":"additional","affiliation":[{"name":"South China Agricultural University (SCAU)","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pin-Xian","family":"Chen","sequence":"additional","affiliation":[{"name":"South China Agricultural University (SCAU)","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong-Xia","family":"Jiang","sequence":"additional","affiliation":[{"name":"South China Agricultural University (SCAU)","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2018,1]]},"reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijantimicag.2005.02.006"},{"key":"e_1_3_3_3_2","doi-asserted-by":"crossref","first-page":"10680","DOI":"10.1074\/jbc.M114.547794","article-title":"beta-Lactam selectivity of multidrug transporters AcrB and AcrD resides in the proximal binding pocket","volume":"289","author":"Kobayashi N.","year":"2014","unstructured":"Kobayashi N., , Tamura N., , van Veen H.W., , Yamaguchi A., , and Murakami S.. 2014. beta-Lactam selectivity of multidrug transporters AcrB and AcrD resides in the proximal binding pocket. J. Biol. Chem., 289:10680\u201310690.","journal-title":"J. Biol. Chem."},{"key":"e_1_3_3_4_2","doi-asserted-by":"crossref","first-page":"627","DOI":"10.1006\/jmbi.1996.0274","article-title":"DNA gyrase and topoisomerase IV on the bacterial chromosome: quinolone-induced DNA cleavage","volume":"258","author":"Chen C.-R.","year":"1996","unstructured":"Chen C.-R., , Malik M., , Snyder M., , and Drlica K.. 1996. DNA gyrase and topoisomerase IV on the bacterial chromosome: quinolone-induced DNA cleavage. J. Mol. Biol., 258:627\u2013637.","journal-title":"J. Mol. Biol."},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.40.10.2380"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.40.4.879"},{"key":"e_1_3_3_7_2","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1093\/jac\/dkg126","article-title":"Relative contributions of the AcrAB, MdfA and NorE efflux pumps to quinolone resistance in Escherichia coli","volume":"51","author":"Yang S.","year":"2003","unstructured":"Yang S., , Clayton S.R., , and Zechiedrich E.L.. 2003. Relative contributions of the AcrAB, MdfA and NorE efflux pumps to quinolone resistance in Escherichia coli. J. Antimicrob. Chemother., 51:545\u2013556.","journal-title":"J. Antimicrob. Chemother."},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00996-10"},{"key":"e_1_3_3_9_2","doi-asserted-by":"crossref","first-page":"306","DOI":"10.1128\/jb.178.1.306-308.1996","article-title":"AcrAB efflux pump plays a major role in the antibiotic resistance phenotype of Escherichia coli multiple-antibiotic-resistance (MAR) mutants","volume":"178","author":"Okusu H.","year":"1996","unstructured":"Okusu H., , Ma D., , and Nikaido H.. 1996. AcrAB efflux pump plays a major role in the antibiotic resistance phenotype of Escherichia coli multiple-antibiotic-resistance (MAR) mutants. J. Bacteriol., 178:306\u2013308.","journal-title":"J. Bacteriol."},{"key":"e_1_3_3_10_2","doi-asserted-by":"crossref","first-page":"2646","DOI":"10.1128\/JB.183.8.2646-2653.2001","article-title":"Suppression of hypersensitivity of Escherichia coli acrB mutant to organic solvents by integrational activation of the acrEF operon with the IS1 or IS2 element","volume":"183","author":"Kobayashi K.","year":"2001","unstructured":"Kobayashi K., , Tsukagoshi N., , and Aono R.. 2001. Suppression of hypersensitivity of Escherichia coli acrB mutant to organic solvents by integrational activation of the acrEF operon with the IS1 or IS2 element. J. Bacteriol., 183:2646\u20132653.","journal-title":"J. Bacteriol."},{"key":"e_1_3_3_11_2","doi-asserted-by":"crossref","first-page":"982","DOI":"10.1093\/jac\/dkt481","article-title":"Redundancy in the periplasmic adaptor proteins AcrA and AcrE provides resilience and an ability to export substrates of multidrug efflux","volume":"69","author":"Smith H.E.","year":"2014","unstructured":"Smith H.E., , and Blair J.M.. 2014. Redundancy in the periplasmic adaptor proteins AcrA and AcrE provides resilience and an ability to export substrates of multidrug efflux. J. Antimicrob. Chemother., 69:982\u2013987.","journal-title":"J. Antimicrob. Chemother."},{"key":"e_1_3_3_12_2","doi-asserted-by":"crossref","first-page":"1611","DOI":"10.1046\/j.1365-2958.2002.02985.x","article-title":"Genomics of the marA\/soxS\/rob regulon of Escherichia coli: identification of directly activated promoters by application of molecular genetics and informatics to microarray data","volume":"44","author":"Martin R.G.","year":"2002","unstructured":"Martin R.G., , and Rosner J.L.. 2002. Genomics of the marA\/soxS\/rob regulon of Escherichia coli: identification of directly activated promoters by application of molecular genetics and informatics to microarray data. Mol. Microbiol., 44:1611\u20131624.","journal-title":"Mol. Microbiol."},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/dkn448"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1089\/mdr.2013.0058"},{"key":"e_1_3_3_15_2","doi-asserted-by":"crossref","first-page":"e365","DOI":"10.1371\/journal.pone.0000365","article-title":"Antibiotic stress, genetic response and altered permeability of E. coli","volume":"2","author":"Viveiros M.","year":"2007","unstructured":"Viveiros M., , Dupont M., , Rodrigues L., , Couto I., , Davin-Regli A., , Martins M., , Page J.-M., , and Amaral L.. 2007. Antibiotic stress, genetic response and altered permeability of E. coli. PLoS One, 2:e365.","journal-title":"PLoS One"},{"key":"e_1_3_3_16_2","doi-asserted-by":"crossref","first-page":"1881","DOI":"10.1099\/mic.0.081166-0","article-title":"The lack of OmpF, but not OmpC, contributes to increased antibiotic resistance in Serratia marcescens","volume":"160","author":"Moya-Torres A.","year":"2014","unstructured":"Moya-Torres A., , Mulvey M.R., , Kumar A., , Oresnik I.J., , and Brassinga A.K.C.. 2014. The lack of OmpF, but not OmpC, contributes to increased antibiotic resistance in Serratia marcescens. Microbiology, 160:1881\u20131892.","journal-title":"Microbiology"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1038\/msb4100050"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.120163297"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.43.9.2131"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.44.7.1771-1777.2000"},{"key":"e_1_3_3_21_2","unstructured":"Clinical and Laboratory Standards Institute (CLSI). 2015. Performance Standards for Antimicrobial Susceptibility Testing; Twenty-Fifth Informational Supplement. Document M100-S25 35. CLSI Wayne PA."},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/29.9.e45"},{"key":"e_1_3_3_23_2","doi-asserted-by":"crossref","first-page":"817","DOI":"10.1016\/j.bbapap.2009.02.017","article-title":"Assembly and transport mechanism of tripartite drug efflux systems","volume":"1794","author":"Misra R.","year":"2009","unstructured":"Misra R., , and Bavro V.N.. 2009. Assembly and transport mechanism of tripartite drug efflux systems. Biochim. Biophys. Acta., 1794:817\u2013825.","journal-title":"Biochim. Biophys. Acta."},{"key":"e_1_3_3_24_2","doi-asserted-by":"crossref","first-page":"32116","DOI":"10.1074\/jbc.M402230200","article-title":"AcrA, AcrB, and TolC of Escherichia coli form a stable intermembrane multidrug efflux complex","volume":"279","author":"Tikhonova E.B.","year":"2004","unstructured":"Tikhonova E.B., , and Zgurskaya H.I.. 2004. AcrA, AcrB, and TolC of Escherichia coli form a stable intermembrane multidrug efflux complex. J. Biol. Chem., 279:32116\u201332124.","journal-title":"J. Biol. Chem."},{"key":"e_1_3_3_25_2","doi-asserted-by":"crossref","first-page":"7173","DOI":"10.1073\/pnas.0900693106","article-title":"The assembled structure of a complete tripartite bacterial multidrug efflux pump","volume":"106","author":"Symmons M.F.","year":"2009","unstructured":"Symmons M.F., , Bokma E., , Koronakis E., , Hughes C., , and Koronakis V.. 2009. The assembled structure of a complete tripartite bacterial multidrug efflux pump. Proc. Natl. Acad. Sci. U.S.A., 106:7173\u20137178.","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"e_1_3_3_26_2","doi-asserted-by":"crossref","first-page":"4365","DOI":"10.1128\/JB.00204-09","article-title":"The C-terminal domain of AcrA is essential for the assembly and function of the multidrug efflux pump AcrAB-TolC","volume":"191","author":"Ge Q.","year":"2009","unstructured":"Ge Q., , Yamada Y., , and Zgurskaya H.. 2009. The C-terminal domain of AcrA is essential for the assembly and function of the multidrug efflux pump AcrAB-TolC. J. Bacteriol., 191:4365\u20134371.","journal-title":"J. Bacteriol."},{"key":"e_1_3_3_27_2","doi-asserted-by":"crossref","first-page":"794","DOI":"10.1016\/j.bbapap.2008.10.010","article-title":"Structural and functional diversity of bacterial membrane fusion proteins","volume":"1794","author":"Zgurskaya H.I.","year":"2009","unstructured":"Zgurskaya H.I., , Yamada Y., , Tikhonova E.B., , Ge Q., , and Krishnamoorthy G.. 2009. Structural and functional diversity of bacterial membrane fusion proteins. Biochim. Biophys. Acta., 1794:794\u2013807.","journal-title":"Biochim. Biophys. Acta."},{"key":"e_1_3_3_28_2","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1038\/nature10641","article-title":"Structures of the multidrug exporter AcrB reveal a proximal multisite drug-binding pocket","volume":"480","author":"Nakashima R.","year":"2011","unstructured":"Nakashima R., , Sakurai K., , Yamasaki S., , Nishino K., , and Yamaguchi A.. 2011. Structures of the multidrug exporter AcrB reveal a proximal multisite drug-binding pocket. Nature, 480:565\u2013570.","journal-title":"Nature"},{"key":"e_1_3_3_29_2","doi-asserted-by":"crossref","first-page":"965","DOI":"10.1111\/mmi.12508","article-title":"Genetic assessment of the role of AcrB \u03b2-hairpins in the assembly of the TolC-AcrAB multidrug efflux pump of Escherichia coli","volume":"91","author":"Jon W. Weeks V.N.B.","year":"2014","unstructured":"Jon W. Weeks V.N.B., and Rajeev Misra. 2014. Genetic assessment of the role of AcrB \u03b2-hairpins in the assembly of the TolC-AcrAB multidrug efflux pump of Escherichia coli. Mol. Microbiol., 91:965\u2013975.","journal-title":"Mol. Microbiol."},{"key":"e_1_3_3_30_2","first-page":"4","article-title":"Repressive mutations restore function-loss caused by the disruption of trimerization in Escherichia coli multidrug transporter AcrB","volume":"6","author":"Wang Z.","year":"2015","unstructured":"Wang Z., , Zhong M., , Lu W., , Chai Q., , and Wei Y.. 2015. Repressive mutations restore function-loss caused by the disruption of trimerization in Escherichia coli multidrug transporter AcrB. Front. Microbiol., 6:4.","journal-title":"Front. Microbiol."},{"key":"e_1_3_3_31_2","doi-asserted-by":"crossref","first-page":"5803","DOI":"10.1128\/jb.178.19.5803-5805.1996","article-title":"Evidence that TolC is required for functioning of the Mar\/AcrAB efflux pump of Escherichia coli","volume":"178","author":"Fralick J.A.","year":"1996","unstructured":"Fralick J.A. 1996. Evidence that TolC is required for functioning of the Mar\/AcrAB efflux pump of Escherichia coli. J. Bacteriol., 178:5803\u20135805.","journal-title":"J. Bacteriol."},{"key":"e_1_3_3_32_2","doi-asserted-by":"crossref","first-page":"914","DOI":"10.1038\/35016007","article-title":"Crystal structure of the bacterial membrane protein TolC central to multidrug efflux and protein export","volume":"405","author":"Koronakis V.","year":"2000","unstructured":"Koronakis V., , Sharff A., , Koronakis E., , Luisi B., , and Hughes C.. 2000. Crystal structure of the bacterial membrane protein TolC central to multidrug efflux and protein export. Nature, 405:914\u2013919.","journal-title":"Nature"},{"key":"e_1_3_3_33_2","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1128\/AAC.50.1.38-42.2006","article-title":"Ciprofloxacin-resistant Salmonella enterica Serovar Typhimurium strains are difficult to select in the absence of AcrB and TolC","volume":"50","author":"Ricci V.","year":"2006","unstructured":"Ricci V., , Tzakas P., , Buckley A., , and Piddock L.J.. 2006. Ciprofloxacin-resistant Salmonella enterica Serovar Typhimurium strains are difficult to select in the absence of AcrB and TolC. Antimicrob. Agents Chemother., 50:38\u201342.","journal-title":"Antimicrob. Agents Chemother."},{"key":"e_1_3_3_34_2","doi-asserted-by":"publisher","DOI":"10.1128\/jb.175.19.6299-6313.1993"},{"key":"e_1_3_3_35_2","doi-asserted-by":"crossref","first-page":"1042","DOI":"10.1128\/JB.01996-12","article-title":"Reduction of cellular stress by TolC-dependent efflux pumps in Escherichia coli indicated by BaeSR and CpxARP activation of spy in efflux mutants","volume":"195","author":"Rosner J.L.","year":"2013","unstructured":"Rosner J.L., , and Martin R.G.. 2013. Reduction of cellular stress by TolC-dependent efflux pumps in Escherichia coli indicated by BaeSR and CpxARP activation of spy in efflux mutants. J. Bacteriol., 195:1042\u20131050.","journal-title":"J. Bacteriol."},{"key":"e_1_3_3_36_2","doi-asserted-by":"publisher","DOI":"10.1128\/JB.183.20.5803-5812.2001"},{"key":"e_1_3_3_37_2","doi-asserted-by":"crossref","first-page":"13836","DOI":"10.1021\/jacs.5b08960","article-title":"Quantification of fluoroquinolone uptake through the outer membrane channel OmpF of Escherichia coli","volume":"137","author":"Cama J.","year":"2016","unstructured":"Cama J., , Bajaj H., , Pagliara S., , Maier T., , Braun Y., , Winterhalter M., , and Keyser U.F.. 2016. Quantification of fluoroquinolone uptake through the outer membrane channel OmpF of Escherichia coli. J. Am. Chem. Soc., 137:13836\u201313843.","journal-title":"J. Am. Chem. Soc."},{"key":"e_1_3_3_38_2","doi-asserted-by":"publisher","DOI":"10.1021\/pr800073c"}],"container-title":["Microbial Drug Resistance"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.sagepub.com\/doi\/full-xml\/10.1089\/mdr.2016.0207","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.sagepub.com\/doi\/pdf\/10.1089\/mdr.2016.0207","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.sagepub.com\/doi\/pdf\/10.1089\/mdr.2016.0207","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T20:31:05Z","timestamp":1777667465000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.sagepub.com\/doi\/full\/10.1089\/mdr.2016.0207"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,1]]},"references-count":37,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2018,1]]}},"alternative-id":["10.1089\/mdr.2016.0207"],"URL":"https:\/\/doi.org\/10.1089\/mdr.2016.0207","relation":{},"ISSN":["1076-6294","1931-8448"],"issn-type":[{"value":"1076-6294","type":"print"},{"value":"1931-8448","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,1]]}}}