{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T14:51:12Z","timestamp":1791298272633,"version":"4.1.0"},"reference-count":43,"publisher":"American Society for Microbiology","issue":"5","license":[{"start":{"date-parts":[[2011,5,1]],"date-time":"2011-05-01T00:00:00Z","timestamp":1304208000000},"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":[[2011,5]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:p>\n            Constitutive AmpC hyperproduction is the most frequent mechanism of resistance to the weak AmpC inducers antipseudomonal penicillins and cephalosporins. Previously, we demonstrated that inhibition of the \u03b2-\n            <jats:italic>N<\/jats:italic>\n            -acetylglucosaminidase NagZ prevents and reverts this mechanism of resistance, which is caused by\n            <jats:italic>ampD<\/jats:italic>\n            and\/or\n            <jats:italic>dacB<\/jats:italic>\n            (PBP4) mutations 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 work, we compared NagZ with a second candidate target, the AmpG permease for GlcNAc-1,6-anhydromuropeptides, for their ability to block AmpC expression pathways. Inactivation of\n            <jats:italic>nagZ<\/jats:italic>\n            or\n            <jats:italic>ampG<\/jats:italic>\n            fully restored the susceptibility and basal\n            <jats:italic>ampC<\/jats:italic>\n            expression of\n            <jats:italic>ampD<\/jats:italic>\n            or\n            <jats:italic>dacB<\/jats:italic>\n            laboratory mutants and impaired the emergence of one-step ceftazidime-resistant mutants in population analysis experiments. Nevertheless, only\n            <jats:italic>ampG<\/jats:italic>\n            inactivation fully blocked\n            <jats:italic>ampC<\/jats:italic>\n            induction, reducing the MICs of the potent AmpC inducer imipenem from 2 to 0.38 \u03bcg\/ml. Moreover, through population analysis and characterization of laboratory mutants, we showed that\n            <jats:italic>ampG<\/jats:italic>\n            inactivation minimized the impact on resistance of the carbapenem porin OprD, reducing the MIC of imipenem for a PAO1 OprD mutant from &gt;32 to 0.5 \u03bcg\/ml. AmpG and NagZ targets were additionally evaluated in three clinical isolates that are pan-\u03b2-lactam resistant due to AmpC hyperproduction, OprD inactivation, and overexpression of several efflux pumps. A marked increase in susceptibility to ceftazidime and piperacillin-tazobactam was observed in both cases, while only\n            <jats:italic>ampG<\/jats:italic>\n            inactivation fully restored wild-type imipenem susceptibility. Susceptibility to meropenem, cefepime, and aztreonam was also enhanced, although to a lower extent due to the high impact of efflux pumps on the activity of these antibiotics. Thus, our results suggest that development of small-molecule inhibitors of AmpG could provide an excellent strategy to overcome the relevant mechanisms of resistance (OprD inactivation plus AmpC induction) to imipenem, the only currently available \u03b2-lactam not significantly affected by\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            major efflux pumps.\n          <\/jats:p>","DOI":"10.1128\/aac.01688-10","type":"journal-article","created":{"date-parts":[[2011,3,1]],"date-time":"2011-03-01T23:32:24Z","timestamp":1299022344000},"page":"1990-1996","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":58,"title":["AmpG Inactivation Restores Susceptibility of Pan-\u03b2-Lactam-Resistant Pseudomonas aeruginosa Clinical Strains"],"prefix":"10.1128","volume":"55","author":[{"given":"Laura","family":"Zamorano","sequence":"first","affiliation":[{"name":"Servicio de Microbiolog\u00eda and Unidad de Investigaci\u00f3n, Hospital Son Espases, Instituto Universitario de Investigaci\u00f3n en Ciencias de la Salud (IUNICS), Palma de Mallorca, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas M.","family":"Reeve","sequence":"additional","affiliation":[{"name":"Department of Microbiology, University of Manitoba, Winnipeg, Manitoba, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlos","family":"Juan","sequence":"additional","affiliation":[{"name":"Servicio de Microbiolog\u00eda and Unidad de Investigaci\u00f3n, Hospital Son Espases, Instituto Universitario de Investigaci\u00f3n en Ciencias de la Salud (IUNICS), Palma de Mallorca, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bartolom\u00e9","family":"Moy\u00e1","sequence":"additional","affiliation":[{"name":"Servicio de Microbiolog\u00eda and Unidad de Investigaci\u00f3n, Hospital Son Espases, Instituto Universitario de Investigaci\u00f3n en Ciencias de la Salud (IUNICS), Palma de Mallorca, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriel","family":"Cabot","sequence":"additional","affiliation":[{"name":"Servicio de Microbiolog\u00eda and Unidad de Investigaci\u00f3n, Hospital Son Espases, Instituto Universitario de Investigaci\u00f3n en Ciencias de la Salud (IUNICS), Palma de Mallorca, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David J.","family":"Vocadlo","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Simon Fraser University, Burnaby, British Columbia, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian L.","family":"Mark","sequence":"additional","affiliation":[{"name":"Department of Microbiology, University of Manitoba, Winnipeg, Manitoba, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonio","family":"Oliver","sequence":"additional","affiliation":[{"name":"Servicio de Microbiolog\u00eda and Unidad de Investigaci\u00f3n, Hospital Son Espases, Instituto Universitario de Investigaci\u00f3n en Ciencias de la Salud (IUNICS), Palma de Mallorca, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01617-08"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2010.05.040"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.39.6.1211"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1128\/JB.182.17.4836-4840.2000"},{"key":"e_1_3_2_6_2","volume-title":"Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically; approved standard","author":"CLSI\/NCCLS.","year":"2003","unstructured":"CLSI\/NCCLS. 2003. 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