{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T22:36:00Z","timestamp":1792794960981,"version":"4.5.0"},"reference-count":41,"publisher":"American Society for Microbiology","issue":"8","license":[{"start":{"date-parts":[[2024,8,6]],"date-time":"2024-08-06T00:00:00Z","timestamp":1722902400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2024,8,6]],"date-time":"2024-08-06T00:00:00Z","timestamp":1722902400000},"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":["Microbiol Spectr"],"published-print":{"date-parts":[[2024,8,6]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:sec>\n            <jats:title\/>\n            <jats:p>\n              The aim of this study was to evaluate the proportion of resistance to a temocillin, tigecycline, ciprofloxacin, and chloramphenicol phenotype called t2c2 that resulted from mutations within the\n              <jats:italic>ramAR<\/jats:italic>\n              locus among extended-spectrum \u03b2-lactamases\n              <jats:italic>-Enterobacterales<\/jats:italic>\n              (ESBL-E) isolated in three intensive care units for 3 years in a French university hospital. Two parallel approaches were performed on all 443 ESBL-E included: (i) the minimal inhibitory concentrations of temocillin, tigecycline, ciprofloxacin, and chloramphenicol were determined and (ii) the genomes obtained from the Illumina sequencing platform were analyzed to determine multilocus sequence types, resistomes, and diversity of several\n              <jats:italic>tetR<\/jats:italic>\n              -associated genes including\n              <jats:italic>ramAR<\/jats:italic>\n              operon. Among the 443 ESBL-E strains included, isolates of\n              <jats:italic>Escherichia coli<\/jats:italic>\n              (\n              <jats:italic>n<\/jats:italic>\n              = 194),\n              <jats:italic>Klebsiella pneumoniae<\/jats:italic>\n              (\n              <jats:italic>n<\/jats:italic>\n              = 122), and\n              <jats:italic>Enterobacter cloacae<\/jats:italic>\n              complex (\n              <jats:italic>Ecc<\/jats:italic>\n              ) (\n              <jats:italic>n<\/jats:italic>\n              = 127) were found. Thirty-one ESBL-E strains (7%), 16\n              <jats:italic>K<\/jats:italic>\n              .\n              <jats:italic>pneumoniae<\/jats:italic>\n              (13.1%), and 15\n              <jats:italic>Ecc<\/jats:italic>\n              (11.8%) presented the t2c2 phenotype in addition to their ESBL profile, whereas no\n              <jats:italic>E. coli<\/jats:italic>\n              presented these resistances. The t2c2 phenotype was invariably reversible by the addition of Phe-Arg-\u03b2-naphthylamide, indicating a role of resistance-nodulation-division pumps in these observations. Mutations associated with the t2c2 phenotype were restricted to RamR, the\n              <jats:italic>ramAR<\/jats:italic>\n              intergenic region (IR), and AcrR. Mutations in RamR consisted of C- or N-terminal deletions and amino acid substitutions inside its DNA-binding domain or within key sites of protein\u2013substrate interactions. The\n              <jats:italic>ramAR<\/jats:italic>\n              IR showed nucleotide substitutions involved in the RamR DNA-binding domain. This diversity of sequences suggested that RamR and the\n              <jats:italic>ramAR<\/jats:italic>\n              IR represent major genetic events for bacterial antimicrobial resistance.\n            <\/jats:p>\n            <jats:sec>\n              <jats:title>IMPORTANCE<\/jats:title>\n              <jats:p>\n                Morbimortality caused by infectious diseases is very high among patients hospitalized in intensive care units (ICUs). A part of these outcomes can be explained by antibiotic resistance, which delays the appropriate therapy. The transferable antibiotic resistance gene is a well-known mechanism to explain the high rate of multidrug resistance (MDR) bacteria in ICUs. This study describes the prevalence of chromosomal mutations, which led to additional antibiotic resistance among MDR bacteria. More than 12% of\n                <jats:italic>Klebsiella pneumoniae<\/jats:italic>\n                and\n                <jats:italic>Enterobacter cloacae<\/jats:italic>\n                complex strains presented mutations within the\n                <jats:italic>ramAR<\/jats:italic>\n                locus associated with a dysregulation of an efflux pump called AcrAB-TolC and a porin: OmpF. These dysregulations led to an increase in antibiotic output notably tigecycline, ciprofloxacin, and chloramphenicol associated with a decrease of input for beta-lactam, especially temocillin. Mutations within transcriptional regulators such as\n                <jats:italic>ramAR<\/jats:italic>\n                locus played a major role in antibiotic resistance dissemination and need to be further explored.\n              <\/jats:p>\n            <\/jats:sec>\n          <\/jats:sec>","DOI":"10.1128\/spectrum.03548-23","type":"journal-article","created":{"date-parts":[[2024,6,25]],"date-time":"2024-06-25T13:01:46Z","timestamp":1719320506000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":8,"title":["Central role of the\n            <i>ramAR<\/i>\n            locus in the multidrug resistance in ESBL\n            <i>-Enterobacterales<\/i>"],"prefix":"10.1128","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8672-8286","authenticated-orcid":true,"given":"Fran\u00e7ois","family":"Gravey","sequence":"first","affiliation":[{"name":"Department of Infectious Agents, Bacteriology, Universit\u00e9 de Caen Normandie, Univ Rouen Normandie, INSERM, Normandie Univ, DYNAMICURE UMR 1311, CHU Caen Normandie, Caen, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alice","family":"Michel","sequence":"additional","affiliation":[{"name":"Univ de Caen Normandie, Univ Rouen Normandie, INSERM, DYNAMICURE UMR 1311, Caen, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"B\u00e9n\u00e9dicte","family":"Langlois","sequence":"additional","affiliation":[{"name":"Department of Infectious Agents, Bacteriology, Universit\u00e9 de Caen Normandie, Univ Rouen Normandie, INSERM, Normandie Univ, DYNAMICURE UMR 1311, CHU Caen Normandie, Caen, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matt\u00e9o","family":"G\u00e9rard","sequence":"additional","affiliation":[{"name":"Univ de Caen Normandie, Univ Rouen Normandie, INSERM, DYNAMICURE UMR 1311, Caen, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S\u00e9bastien","family":"Galopin","sequence":"additional","affiliation":[{"name":"Univ de Caen Normandie, Univ Rouen Normandie, INSERM, DYNAMICURE UMR 1311, Caen, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cl\u00e9ment","family":"Gakuba","sequence":"additional","affiliation":[{"name":"Service de R\u00e9animation Chirurgicale, Univ de Caen Normandie, CHU de Caen Normandie, Caen, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Damien","family":"Du Cheyron","sequence":"additional","affiliation":[{"name":"Service de R\u00e9animation M\u00e9dicale, Univ de Caen Normandie, CHU de Caen Normandie, Caen, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Fazilleau","sequence":"additional","affiliation":[{"name":"Service de R\u00e9animation N\u00e9onatale, Univ de Caen Normandie, CHU de Caen Normandie, Caen, 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