{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T02:17:33Z","timestamp":1791166653961,"version":"4.1.0"},"reference-count":54,"publisher":"American Society for Microbiology","issue":"1","license":[{"start":{"date-parts":[[2014,1,1]],"date-time":"2014-01-01T00:00:00Z","timestamp":1388534400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Antimicrob Agents Chemother"],"published-print":{"date-parts":[[2014,1]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Constitutive overproduction of the pump MexXY-OprM is recognized as a major cause of resistance to aminoglycosides, fluoroquinolones, and zwitterionic cephalosporins in\n                    <jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">Pseudomonas aeruginosa<\/jats:named-content>\n                    . In this study, 57 clonally unrelated strains recovered from non-cystic fibrosis patients were analyzed to characterize the mutations resulting in upregulation of the\n                    <jats:italic>mexXY<\/jats:italic>\n                    operon. Forty-four (77.2%) of the strains, classified as\n                    <jats:italic>agrZ<\/jats:italic>\n                    mutants were found to harbor mutations inactivating the local repressor gene (\n                    <jats:italic>mexZ<\/jats:italic>\n                    ) of the\n                    <jats:italic>mexXY<\/jats:italic>\n                    operon (\n                    <jats:italic>n<\/jats:italic>\n                    = 33; 57.9%) or introducing amino acid substitutions in its product, MexZ (\n                    <jats:italic>n<\/jats:italic>\n                    = 11; 19.3%). These sequence variations, which mapped in the dimerization domain, the DNA binding domain, or the rest of the MexZ structure, mostly affected amino acid positions conserved in TetR-like regulators. The 13 remaining MexXY-OprM strains (22.8%) contained intact\n                    <jats:italic>mexZ<\/jats:italic>\n                    genes encoding wild-type MexZ proteins. Eight (14.0%) of these isolates, classified as\n                    <jats:italic>agrW1<\/jats:italic>\n                    mutants, overexpressed the gene PA5471, which codes for the MexZ antirepressor AmrZ, with 5 strains exhibiting growth defects at 37\u00b0C and 44\u00b0C, consistent with mutations impairing ribosome activity. Interestingly, one\n                    <jats:italic>agrW1<\/jats:italic>\n                    mutant appeared to harbor a 7-bp deletion in the coding sequence of the leader peptide, PA5471.1, involved in ribosome-dependent, translational attenuation of PA5471 expression. Finally, DNA sequencing and complementation experiments revealed that 5 (8.8%) strains, classified as\n                    <jats:italic>agrW2<\/jats:italic>\n                    mutants, harbored single amino acid variations in the sensor histidine kinase of ParRS, a two-component system known to positively control\n                    <jats:italic>mexXY<\/jats:italic>\n                    expression. Collectively, these results demonstrate that clinical strains of\n                    <jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">P. aeruginosa<\/jats:named-content>\n                    exploit different regulatory circuitries to mutationally overproduce the MexXY-OprM pump and become multidrug resistant, which accounts for the high prevalence of MexXY-OprM mutants in the clinical setting.\n                  <\/jats:p>","DOI":"10.1128\/aac.01252-13","type":"journal-article","created":{"date-parts":[[2013,10,21]],"date-time":"2013-10-21T22:41:14Z","timestamp":1382395274000},"page":"221-228","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":118,"title":["Multiple Mutations Lead to MexXY-OprM-Dependent Aminoglycoside Resistance in Clinical Strains of Pseudomonas aeruginosa"],"prefix":"10.1128","volume":"58","author":[{"given":"Sophie","family":"Gu\u00e9nard","sequence":"first","affiliation":[{"name":"Centre National de R\u00e9f\u00e9rence de la R\u00e9sistance aux Antibiotiques, Centre Hospitalier R\u00e9gional Universitaire de Besan\u00e7on, Universit\u00e9 de Franche-Comt\u00e9, Besan\u00e7on, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C\u00e9dric","family":"Muller","sequence":"additional","affiliation":[{"name":"Centre National de R\u00e9f\u00e9rence de la R\u00e9sistance aux Antibiotiques, Centre Hospitalier R\u00e9gional Universitaire de Besan\u00e7on, Universit\u00e9 de Franche-Comt\u00e9, Besan\u00e7on, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Monlezun","sequence":"additional","affiliation":[{"name":"Laboratoire de Cristallographie et RMN Biologiques, CNRS Universit\u00e9 Paris Descartes, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philippe","family":"Benas","sequence":"additional","affiliation":[{"name":"Laboratoire de Cristallographie et RMN Biologiques, CNRS Universit\u00e9 Paris Descartes, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabelle","family":"Broutin","sequence":"additional","affiliation":[{"name":"Laboratoire de Cristallographie et RMN Biologiques, CNRS Universit\u00e9 Paris Descartes, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katy","family":"Jeannot","sequence":"additional","affiliation":[{"name":"Centre National de R\u00e9f\u00e9rence de la R\u00e9sistance aux Antibiotiques, Centre Hospitalier R\u00e9gional Universitaire de Besan\u00e7on, Universit\u00e9 de Franche-Comt\u00e9, Besan\u00e7on, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick","family":"Pl\u00e9siat","sequence":"additional","affiliation":[{"name":"Centre 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