{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T14:51:51Z","timestamp":1791298311328,"version":"4.1.0"},"reference-count":43,"publisher":"American Society for Microbiology","issue":"5","license":[{"start":{"date-parts":[[2006,5,1]],"date-time":"2006-05-01T00:00:00Z","timestamp":1146441600000},"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":[[2006,5]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Development of resistance to the antipseudomonal penicillins and cephalosporins mediated by hyperproduction of the chromosomal cephalosporinase AmpC is a major threat to the successful treatment of\n                    <jats:italic>Pseudomonas aeruginosa<\/jats:italic>\n                    infections. Although\n                    <jats:italic>ampD<\/jats:italic>\n                    inactivation has been previously found to lead to a partially derepressed phenotype characterized by increased AmpC production but retaining further inducibility, the regulation of\n                    <jats:italic>ampC<\/jats:italic>\n                    in\n                    <jats:italic>P. aeruginosa<\/jats:italic>\n                    is far from well understood. We demonstrate that\n                    <jats:italic>ampC<\/jats:italic>\n                    expression is coordinately repressed by three AmpD homologues, including the previously described protein AmpD plus two additional proteins, designated AmpDh2 and AmpDh3. The three AmpD homologues are responsible for a stepwise\n                    <jats:italic>ampC<\/jats:italic>\n                    upregulation mechanism ultimately leading to constitutive hyperexpression of the chromosomal cephalosporinase and high-level antipseudomonal \u03b2-lactam resistance, as shown by analysis of the three single\n                    <jats:italic>ampD<\/jats:italic>\n                    mutants, the three double\n                    <jats:italic>ampD<\/jats:italic>\n                    mutants, and the triple\n                    <jats:italic>ampD<\/jats:italic>\n                    mutant. This is achieved by a three-step escalating mechanism rendering four relevant expression states: basal-level inducible expression (wild type), moderate-level hyperinducible expression with increased antipseudomonal \u03b2-lactam resistance (\n                    <jats:italic>ampD<\/jats:italic>\n                    mutant), high-level hyperinducible expression with high-level \u03b2-lactam resistance (\n                    <jats:italic>ampD ampDh3<\/jats:italic>\n                    double mutant), and very high-level (more than 1,000-fold compared to the wild type) derepressed expression (triple mutant). Although one-step inducible-derepressed expression models are frequent in natural resistance mechanisms, this is the first characterized example in which expression of a resistance gene can be sequentially amplified through multiple steps of derepression.\n                  <\/jats:p>","DOI":"10.1128\/aac.50.5.1780-1787.2006","type":"journal-article","created":{"date-parts":[[2006,4,26]],"date-time":"2006-04-26T18:58:47Z","timestamp":1146077927000},"page":"1780-1787","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":160,"title":["Stepwise Upregulation of the\n                    <i>Pseudomonas aeruginosa<\/i>\n                    Chromosomal Cephalosporinase Conferring High-Level \u03b2-Lactam Resistance Involves Three AmpD Homologues"],"prefix":"10.1128","volume":"50","author":[{"given":"Carlos","family":"Juan","sequence":"first","affiliation":[{"name":"Servicio de Microbiologi\u0301a, Hospital Son Dureta, Palma de Mallorca, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bartolome\u0301","family":"Moya\u0301","sequence":"additional","affiliation":[{"name":"Servicio de Microbiologi\u0301a, Hospital Son Dureta, Palma de Mallorca, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jose\u0301 L.","family":"Pe\u0301rez","sequence":"additional","affiliation":[{"name":"Servicio de Microbiologi\u0301a, Hospital Son Dureta, Palma de Mallorca, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonio","family":"Oliver","sequence":"additional","affiliation":[{"name":"Servicio de Microbiologi\u0301a, Hospital Son Dureta, 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.46.11.3406-3411.2002"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.48.4.1175-1187.2004"},{"key":"e_1_3_2_4_2","first-page":"376","volume":"5","year":"1987","unstructured":"Bullock, W. O., J. M. Fernandez, and J. M. Short. 1987. XL1 Blue: a high efficiency plasmid transforming recA Escherichia coli strain with \u03b2-galactosidase selection. BioTechniques5:376-378.","journal-title":"BioTechniques"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.39.6.1211"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.43.6.1379"},{"key":"e_1_3_2_7_2","unstructured":"Clinical and Laboratory Standards Institute. 2005. Performance standards for antimicrobial susceptibility testing. Fifteenth informational supplement M100-S15. Clinical and Laboratory Standards Institute Wayne Pa."},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.41.10.2113"},{"key":"e_1_3_2_9_2","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1002\/j.1875-9114.1995.tb04366.x","volume":"15","year":"1995","unstructured":"Fish, D. N., S. C. Piscitelli, and L. H. Danziger. 1995. Development of resistance during antimicrobial therapy: a review of antibiotic classes and patient characteristics in 173 studies. Pharmacotherapy15:279-291.","journal-title":"Pharmacotherapy"},{"key":"e_1_3_2_10_2","first-page":"147","volume":"7","year":"2005","unstructured":"Folkesson, F., S. Eriksson, M. Andersson, J. T. Park, and S. Normark. 2005. Components of the peptidoglycan-recycling pathway modulate invasion and intracellular survival of Salmonella enterica serovar Typhimurium. Cell. Microbiol.7:147-155.","journal-title":"Cell. Microbiol."},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1042\/bj20030862"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.48.6.2043-2048.2004"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/26.2.247"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1128\/mr.60.3.539-574.1996"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1574-6968.1994.tb07159.x"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1002\/j.1460-2075.1986.tb04704.x"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2958.1989.tb00262.x"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1002\/j.1460-2075.1994.tb06792.x"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1469-0691.2005.01251.x"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.49.11.4733-4738.2005"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.gene.2005.05.027"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.49.11.4567-4575.2005"},{"key":"e_1_3_2_23_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.33.11.1946"},{"key":"e_1_3_2_24_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.42.12.3296"},{"key":"e_1_3_2_25_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.44.3.583-589.2000"},{"key":"e_1_3_2_26_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.82.14.4620"},{"key":"e_1_3_2_27_2","doi-asserted-by":"publisher","DOI":"10.1128\/jb.169.5.1923-1928.1987"},{"key":"e_1_3_2_28_2","doi-asserted-by":"publisher","DOI":"10.1007\/BF02013107"},{"key":"e_1_3_2_29_2","doi-asserted-by":"publisher","DOI":"10.1128\/CMR.8.4.557"},{"key":"e_1_3_2_30_2","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/48.suppl_1.59"},{"key":"e_1_3_2_31_2","doi-asserted-by":"publisher","DOI":"10.1086\/338782"},{"key":"e_1_3_2_32_2","first-page":"315","volume":"111","year":"1993","unstructured":"Lodge, J., S. Busby, and L. Piddock. 1993. Investigation of the Pseudomonas aeruginosa ampR gene and its role at the chromosomal ampC promoter. FEMS Microbiol. Lett.111:315-320.","journal-title":"FEMS Microbiol. Lett."},{"key":"e_1_3_2_33_2","doi-asserted-by":"publisher","DOI":"10.2144\/02335rr01"},{"key":"e_1_3_2_34_2","doi-asserted-by":"publisher","DOI":"10.1089\/mdr.1995.1.111"},{"key":"e_1_3_2_35_2","doi-asserted-by":"publisher","DOI":"10.1128\/JB.182.17.4829-4835.2000"},{"key":"e_1_3_2_36_2","first-page":"323","volume":"8","year":"2003","unstructured":"Oh, H., J. Stenhoff, S. Jalal, and B. Wretlind. 2003. Role of efflux pumps and mutations in genes for topoisomerases II and IV in fluoroquinolone-resistant Pseudomonas aeruginosa strains. Microb. Drug Resist.8:323-328.","journal-title":"Microb. Drug Resist."},{"key":"e_1_3_2_37_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.288.5469.1251"},{"key":"e_1_3_2_38_2","doi-asserted-by":"publisher","DOI":"10.2144\/05381ST01"},{"key":"e_1_3_2_39_2","doi-asserted-by":"publisher","DOI":"10.1038\/nbt1183-784"},{"key":"e_1_3_2_40_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/17.24.10509"},{"key":"e_1_3_2_41_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.39.11.2494"},{"key":"e_1_3_2_42_2","doi-asserted-by":"publisher","DOI":"10.1038\/35023079"},{"key":"e_1_3_2_43_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(03)13644-6"},{"key":"e_1_3_2_44_2","doi-asserted-by":"publisher","DOI":"10.1016\/0378-1119(94)90237-2"}],"container-title":["Antimicrobial Agents and Chemotherapy"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/AAC.50.5.1780-1787.2006","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/AAC.50.5.1780-1787.2006","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,2,3]],"date-time":"2024-02-03T19:48:09Z","timestamp":1706989689000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.asm.org\/doi\/10.1128\/AAC.50.5.1780-1787.2006"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2006,5]]},"references-count":43,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2006,5]]}},"alternative-id":["10.1128\/AAC.50.5.1780-1787.2006"],"URL":"https:\/\/doi.org\/10.1128\/aac.50.5.1780-1787.2006","relation":{},"ISSN":["0066-4804","1098-6596"],"issn-type":[{"value":"0066-4804","type":"print"},{"value":"1098-6596","type":"electronic"}],"subject":[],"published":{"date-parts":[[2006,5]]},"assertion":[{"value":"2006-01-07","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2006-03-06","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2006-05-01","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}