Altered Outer Membrane Transcriptome Balance with AmpC Overexpression in Carbapenem-Resistant Enterobacter cloacae

Majewski, Piotr; Wieczorek, Piotr; Ojdana, Dominika; Sieńko, Anna; Kowalczuk, Oksana; Sacha, Paweł; Nikliński, Jacek; Tryniszewska, Elżbieta

doi:10.3389/fmicb.2016.02054

Cited by 35 publications

(37 citation statements)

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“…Therefore, an additional factor contributing to the carbapenem resistance of isolate 1 could be the absence of an outer membrane porin, especially OmpF. The latter would be consistent with previous studies on the role of porins in the resistance of Enterobacteriaceae to antibiotics [29,39,40]. …”

Section: Discussionsupporting

confidence: 88%

An ancient family of mobile genomic islands introducing cephalosporinase and carbapenemase genes in Enterobacteriaceae

et al. 2018

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The exchange of mobile genomic islands (MGIs) between microorganisms is often mediated by phages, which may provide benefits to the phage’s host. The present study started with the identification of Enterobacter cloacae, Klebsiella pneumoniae and Escherichia coli isolates with exceptional cephalosporin and carbapenem resistance phenotypes from patients in a neonatal ward. To identify possible molecular connections between these isolates and their β-lactam resistance phenotypes, the respective bacterial genome sequences were compared. This unveiled the existence of a family of ancient MGIs that were probably exchanged before the species E. cloacae, K. pneumoniae and E. coli emerged from their common ancestry. A representative MGI from E. cloacae was named MIR17-GI, because it harbors the novel β-lactamase gene variant blaMIR17. Importantly, our observations show that the MIR17-GI-like MGIs harbor genes associated with high-level resistance to cephalosporins. Among them, MIR17-GI stands out because MIR17 also displays carbapenemase activity. As shown by mass spectrometry, the MIR17 carbapenemase is among the most abundantly expressed proteins of the respective E. cloacae isolate. Further, we show that MIR17-GI-like islands are associated with integrated P4-like prophages. This implicates phages in the spread of cephalosporin and carbapenem resistance amongst Enterobacteriaceae. The discovery of an ancient family of MGIs, mediating the spread of cephalosporinase and carbapenemase genes, is of high clinical relevance, because high-level cephalosporin and carbapenem resistance have serious implications for the treatment of patients with enterobacteriaceal infections.

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Section: Discussionsupporting

confidence: 88%

An ancient family of mobile genomic islands introducing cephalosporinase and carbapenemase genes in Enterobacteriaceae

et al. 2018

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“…Though ompF was found to be slightly underexpressed in meropenem after 30 minutes with respect to untreated conditions, the lack of differential expression in the ertapenem-treated conditions leads us to conclude that transcriptomic control of this gene is not a major resistance factor for E. coli CUS2B. As discussed above, the downregulation and deletion of these genes has previously been linked to carbapenem-resistance, 19, 33, 42, 67 but, if this mechanism is active in E. coli CUS2B, it does not appear to be regulated by transient gene expression. Similarly, none of the resistance-related genes identified in our genomic analysis were found to be DE in any carbapenem treatment condition, and we may conclude that transcriptomic control of these genes does not contribute to the E. coli CUS2B resistance phenotype.…”

Section: Discussionmentioning

confidence: 76%

“…E. coli CUS2B also encodes the outer membrane porins OmpA, OmpC, and OmpF, the mutation or downregulation of which may influence carbapenem efficacy. 19, 33, 42 These three proteins have, respectively, 95%, 90%, and 90% nucleotide homology with the corresponding genes in E. coli MG1655.…”

Section: Resultsmentioning

confidence: 98%

“…We also searched for differential expression in outer membrane porin operon ( omp ) genes, previously linked to carbapenem-resistance, 19, 33, 42 and resistance-related genes identified by ARG-ANNOT. Of the omp operon, only ompF was found to be significantly DE in any condition with respect to no treatment (underexpressed in meropenem, 30 minutes) (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…The basal expression of AmpC in wild-type E. coli is not enough to confer resistance to beta-lactams, but mutation-induced overproduction of the chromosomal AmpC in Enterobacteriaceae has been shown to promote antibiotic resistance. 33, 42, 69–71 Furthermore, when coupled with porin deficiencies, AmpC expression can increase enterobacterial resistance to ertapenem while retaining susceptibility to other carbapenems. 23, 67, 68, 72, 73 Our genomic analysis identified ten codon mutations in the E. coli CUS2B AmpC compared with E. coli MG1655, as well as four nucleotide mutations in the −35 to −10 promoter region.…”

Section: Discussionmentioning

confidence: 99%

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Transcriptome-based design of antisense inhibitors re-sensitizes CREE. colito carbapenems

Aunins

Erickson

Chatterjee

2019

Preprint

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12Carbapenems are a powerful class of antibiotics, often used as a last-resort treatment to eradicate 13 multidrug-resistant infections. In recent years, however, the incidence of carbapenem-resistant 14Enterobacteriaceae (CRE) has risen substantially, and the study of bacterial resistance 15 mechanisms has become increasingly important for antibiotic development. Although much 16 research has focused on genomic contributors to carbapenem resistance, relatively few studies 17 have examined CRE pathogens through changes in gene expression. In this research, we used 18 transcriptomics to study a CRE Escherichia coli clinical isolate that is sensitive to meropenem but 19 resistant to ertapenem, to both explore carbapenem resistance and identify novel gene 20 knockdown targets for carbapenem re-sensitization. We sequenced total and small RNA to 21 analyze gene expression changes in response to treatment with ertapenem or meropenem, as 22Keywords: Carbapenem-resistant E. coli, transcriptome, small RNA sequencing, genome 36 sequence, antibiotic resistance. 37 through the expression of low-affinity or mutated penicillin-binding proteins, [24][25][26][27] or through the 62 overproduction of efflux pumps. 28,29 63 Other research has sought to understand resistance by tracking transcriptomic changes 64 in carbapenem-resistant pathogens. Two studies on the gene expression profile of carbapenem-65 resistant Acinetobacter baumanii found significant upregulation of transposable elements, 66 recombinase, and other mutation-encouraging factors, in addition to the expected upregulation of 67 efflux pump and β-lactamase genes. 30,31 Four recent studies that examined transcriptomic profiles 68 of CRE-Enterobacter cloacae, K. pneumoniae (2), and Escherichia coli-identified less 69 consistent responses, although downregulation of porin genes and upregulation of cell survival 70 and β-lactamase genes were observed. 32-35 Of this prior research, only one study 32 attempts to 71 evaluate the transcriptomic response of a resistant Enterobacteriaceae strain under antibiotic 72 challenge, the majority examining only the constitutive gene expression levels of an untreated 73 resistant pathogen. 74In this study, we both explore and counter carbapenem resistance by examining the short-75 term (<1 hr) transient transcriptomic response of a clinical isolate of multidrug resistant (MDR) E. 76 coli (referred to from here as E. coli CUS2B) to carbapenem treatment. The strain demonstrates 77 resistance to ertapenem, but sensitivity to meropenem and doripenem, and we sought to use this 78 partial carbapenem resistance phenotype to help understand the development of resistance in 79Enterobacteriaceae. We used a combination of total and small RNA sequencing to assess the 80 response of E. coli CUS2B to either ertapenem or meropenem treatment and identify genes that 81 were potentially important to the pathogen's resistance profile. We then used these genes, 82together with genome sequencing of the clinical isolate, as inputs for the FAST platform. 36 ...

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Factors associated with non-carbapenemase mediated carbapenem resistance of Gram-negative bacteria: a retrospective case-control study

et al. 2023

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Infections with carbapenemase-producing Gram-negative bacteria are related to increased morbidity and mortality, yet little is known regarding infections caused by non-beta-lactamase mediated carbapenem-resistant bacteria. Our objective was to identify risk factors for, and the clinical impact of infections caused by carbapenem-resistant carbapenemase-negative Enterobacterales and Pseudomonas aeruginosa. This retrospective matched case-control study was performed at the University Hospital of Basel, Switzerland, in 2016. We focused on other resistance mechanisms by excluding laboratory-confirmed carbapenemase-positive cases. Carbapenem resistance was set as the primary endpoint, and important risk factors were investigated by conditional logistic regression. The clinical impact of carbapenem resistance was estimated using regression models containing the resistance indicator as explanatory factor and adjusting for potential confounders. Seventy-five cases of infections with carbapenem-resistant, carbapenemase-negative bacteria were identified and matched with 75 controls with carbapenem-susceptible infections. The matched data set was well-balanced regarding age, gender, and comorbidity. Duration of prior carbapenem treatment (OR 1.15, [1.01, 1.31]) correlated with resistance to carbapenems. Our study showed that patients with carbapenem-resistant bacteria stayed 1.59 times (CI [0.81, 3.14]) longer in an ICU. The analyzed dataset did not provide evidence for strong clinical implications of resistance to carbapenems or increased mortality. The duration of prior carbapenem treatment seems to be a strong risk factor for the development of carbapenem resistance. The higher risk for a longer ICU stay could be a consequence of a carbapenem resistance. In contrast to carbapenemase-producers, the clinical impact of carbapenamase-negative, carbapenem-resistant strains may be limited. Trial registration: The study design was prospectively approved by the local Ethics Commission on 10.08.2017 (EKNZ BASEC 2017-00222).

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Altered Outer Membrane Transcriptome Balance with AmpC Overexpression in Carbapenem-Resistant Enterobacter cloacae

Cited by 35 publications

References 84 publications

An ancient family of mobile genomic islands introducing cephalosporinase and carbapenemase genes in Enterobacteriaceae

An ancient family of mobile genomic islands introducing cephalosporinase and carbapenemase genes in Enterobacteriaceae

Transcriptome-based design of antisense inhibitors re-sensitizes CREE. colito carbapenems

Factors associated with non-carbapenemase mediated carbapenem resistance of Gram-negative bacteria: a retrospective case-control study

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