IS26-mediated amplification of blaOXA-1and blaCTX-M-15with concurrent outer membrane porin disruption associated with de novo carbapenem resistance in a recurrent bacteraemia cohort

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dc.contributor.authorShropshire, William C.
dc.contributor.authorAitken, Samuel L.
dc.contributor.authorReed, Pifer
dc.contributor.authorKim, Jiwoong
dc.contributor.authorMicah M., Bhatti
dc.contributor.authorLi, Xiqi
dc.contributor.authorKalia, Awdhesh
dc.contributor.authorGalloway-Peña, Jessica R.
dc.contributor.authorSahasrabhojane, Pranoti V.
dc.contributor.authorArias, Cesar A.
dc.contributor.authorGreenberg, David E.
dc.contributor.authorHanson, Blake M.
dc.contributor.authorShelburne, Samuel A.
dc.date.accessioned2021-04-09T16:30:46Z
dc.date.available2021-04-09T16:30:46Z
dc.date.issued2021-02-01
dc.description.abstractenglishBackground: Approximately half of clinical carbapenem-resistant Enterobacterales (CRE) isolates lack carbapenem-hydrolysing enzymes and develop carbapenem resistance through alternative mechanisms. Objectives: To elucidate development of carbapenem resistance mechanisms from clonal, recurrent ESBL-positive Enterobacterales (ESBL-E) bacteraemia isolates in a vulnerable patient population. Methods: This study investigated a cohort of ESBL-E bacteraemia cases in Houston, TX, USA. Oxford Nanopore Technologies long-read and Illumina short-read sequencing data were used for comparative genomic analysis. Serial passaging experiments were performed on a set of clinical ST131 Escherichia coli isolates to recapitulate in vivo observations. Quantitative PCR (qPCR) and qRT-PCR were used to determine copy number and transcript levels of β-lactamase genes, respectively. Results: Non-carbapenemase-producing CRE (non-CP-CRE) clinical isolates emerged from an ESBL-E background through a concurrence of primarily IS26-mediated amplifications of blaOXA-1 and blaCTX-M-1 group genes coupled with porin inactivation. The discrete, modular translocatable units (TUs) that carried and amplified β-lactamase genes mobilized intracellularly from a chromosomal, IS26-bound transposon and inserted within porin genes, thereby increasing β-lactamase gene copy number and inactivating porins concurrently. The carbapenem resistance phenotype and TU-mediated β-lactamase gene amplification were recapitulated by passaging a clinical ESBL-E isolate in the presence of ertapenem. Clinical non-CP-CRE isolates had stable carbapenem resistance phenotypes in the absence of ertapenem exposure. Conclusions: These data demonstrate IS26-mediated mechanisms underlying β-lactamase gene amplification with concurrent outer membrane porin disruption driving emergence of clinical non-CP-CRE. Furthermore, these amplifications were stable in the absence of antimicrobial pressure. Long-read sequencing can be utilized to identify unique mobile genetic element mechanisms that drive antimicrobial resistance.eng
dc.format.mimetypeapplication/pdf
dc.identifier.doihttps://doi.org/10.1093/jac/dkaa447
dc.identifier.instnameinstname:Universidad El Bosquespa
dc.identifier.issn1460-2091
dc.identifier.reponamereponame:Repositorio Institucional Universidad El Bosquespa
dc.identifier.repourlrepourl:https://repositorio.unbosque.edu.co
dc.identifier.urihttps://hdl.handle.net/20.500.12495/5743
dc.language.isoeng
dc.publisherOxford University Pressspa
dc.publisher.journalJournal of antimicrobial chemotherapyspa
dc.relation.ispartofseriesJournal of antimicrobial chemotherapy, 1460-2091, Vol. 76, Nro. 2, 2021, p. 385-395spa
dc.relation.urihttps://academic.oup.com/jac/article-abstract/76/2/385/5961599?redirectedFrom=fulltext
dc.rights.accessrightshttps://purl.org/coar/access_right/c_abf2
dc.rights.accessrightsinfo:eu-repo/semantics/openAccess
dc.rights.accessrightsAcceso abierto
dc.rights.localAcceso abiertospa
dc.subject.decsBeta-Lactamasasspa
dc.subject.decsEnterobacteriaceae resistentes a los carbapenémicosspa
dc.subject.decscarbapenémicosspa
dc.titleIS26-mediated amplification of blaOXA-1and blaCTX-M-15with concurrent outer membrane porin disruption associated with de novo carbapenem resistance in a recurrent bacteraemia cohortspa
dc.title.translatedIS26-mediated amplification of blaOXA-1and blaCTX-M-15with concurrent outer membrane porin disruption associated with de novo carbapenem resistance in a recurrent bacteraemia cohortspa
dc.type.coarhttps://purl.org/coar/resource_type/c_6501
dc.type.driverinfo:eu-repo/semantics/article
dc.type.hasversioninfo:eu-repo/semantics/publishedVersion
dc.type.localArtículo de revista

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