Ontology highlight
ABSTRACT:
PROVIDER: PRJNA940390 | ENA |
REPOSITORIES: ENA
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Project description:The emergence of polymyxin resistance in carbapenem-resistant and extended-spectrum -lactamase (ESBL)-producing bacteria is a critical threat to human health, and new treatment strategies are urgently required. Here, we investigated the ability of the safe-for-human use ionophore PBT2 to restore antibiotic sensitivity in polymyxin-resistant, ESBL-producing, carbapenem-resistant Gram-negative human pathogens. PBT2 was observed to resensitize Klebsiella pneumoniae, Escherichia coli, Acinetobacter baumannii and Pseudomonas aeruginosa to last-resort polymyxin class antibiotics, including the less-toxic next-generation polymyxin derivative, FADDI-287. We were unable to select for mutants resistant to PBT2 + FADDI-287 in polymyxin resistant E. coli containing a plasmid-borne mcr-1 gene or K. pneumoniae carrying a chromosomal mgrB mutation. Using a highly invasive K. pneumoniae strain engineered for polymyxin resistance through mgrB mutation, we successfully demonstrated the efficacy of PBT2 + FADDI-287 in vivo for the treatment of Gram-negative sepsis. These data present a new treatment modality to break antibiotic resistance in high priority polymyxin-resistant Gram-negative pathogens.
2020-07-01 | GSE153553 | GEO
Project description:Carbapenem resistant enterobacteriales in a hospital ward
| PRJEB38983 | ENA
Project description:The emergence of colistin resistance in carbapenem-resistant and extended-spectrum ß-lactamase (ESBL)-producing bacteria is a significant threat to human health, and new treatment strategies are urgently required. Here we investigated the ability of the safe-for-human use ionophore PBT2 to restore antibiotic sensitivity in several polymyxin-resistant, ESBL-producing, carbapenem resistant Gram-negative human pathogens. PBT2 was observed to resensitize Klebsiella pneumoniae, Escherichia coli, Acinetobacter baumannii, and Pseudomonas aeruginosa to last-resort polymyxin class antibiotics, including a ‘next generation’ polymyxin derivative, FADDI-287. To gain additional insight into the potential mechanism of action of PBT2, we analyzed the transcriptome of K. pneumoniae and E. coli in the presence of sub-inhibitory concentrations of PBT2. Treatment with PBT2 was associated with multiple stress responses in both K. pneumoniae and E. coli. Significant changes in the transcription of transition metal ion homeostasis genes were observed in both strains.
2019-06-13 | GSE132637 | GEO
Project description:Infections caused by carbapenem-resistant Acinetobacter baumannii (CRAb) are associated with high patient morbidity and mortality. The serious threat for human health imposed by CRAb was recently underscored by identification of close-to-untouchable carbapenem- and tetracycline-resistant isolates. Since outer membrane vesicles (OMVs) of Gram-negative bacteria may contribute to antimicrobial resistance, our present study was aimed at investigating OMVs produced by the first two carbapenem- and tetracycline-resistant CRAb isolates in Europe. These isolates, denoted CRAb1 and CRAb2 contain large, nearly identical plasmids that specify multiple resistances. Both isolates produce OMVs that were analyzed by differential light scattering, transmission electron microscopy and proteomics. By comparison with OMVs from the plasmid-free non-carbapenem-resistant A. baumannii isolate Ab1, which is an isogenic ancestor of the CRAb1 isolate, we show that plasmid carriage by the CRAb1 and CRAb2 isolates leads to an increased OMV size that is accompanied by increased diversity of the OMV proteome. Our analyses show that OMVs from CRAb1 and CRAb2 are major reservoirs of proteins involved in antimicrobial resistance, including the plasmid-encoded carbapenemases BlaNDM-1, and BlaOXA-97. We also show that these OMV-borne carbapenemases hydrolyze imipenem and protect otherwise carbapenem-sensitive A. baumannii and Escherichia coli isolates against this antibiotic. Altogether, our observations show that OMVs from highly drug-resistant CRAb confer tolerance against last-resort antibiotics to non-resistant bacterial pathogens.
2025-04-14 | PXD051698 | Pride
Project description:This study aims to determine the epidemiology of Enterobacteriaceae resistant to antibiotics of last resort in pregnant women in labour at a tertiary hospital, Pretoria, South Africa. Rectal swabs shall be used to screen for colonisation with CRE and colistin-resistant Enterobacteriales in pregnant women during labour. Carbapenem and colistin-resistant Enterobacterales can cause the following infections: bacteraemia; nosocomial pneumonia; urinary tract infections, and intra-abdominal infections. Due to limited treatment options, infections caused by these multidrug-resistant organisms are associated with a mortality rate of 40-50%. Screening for colonisation of carbapenem-resistant Enterobacteriaceae (CRE) and colistin-resistant Enterobacteriaceae will help implement infection and prevention measures to limit the spread of these multidrug-resistant organisms.
2022-07-20 | GSE208573 | GEO
Project description:Both NK cells and group 3 ILCs play key roles and that effector cytokines made by these cells can provide immunoprophylaxis against Carbapenem resistant K. pneumoniae infection.
2020-05-13 | GSE130045 | GEO
Project description:Background: Efflux pumps are important cofactors for carbapenem resistance in Enterobacter cloacae. The regulatory mechanism by which asmA influences efflux pump function in this species remains unclear. This study explored the regulatory role of asmA on efflux pumps in carbapenem-resistant Enterobacter cloacae. Results: Sixteen carbapenem-resistant Enterobacter cloacae were collected. All strains carried blaNDM, 87.5% of which were blaNDM-1 and 12.5% were blaNDM-5. PAβN had weak inhibition on carbapenem resistance in ST78 and strong inhibition in ST2260. ST2260(CY-8) was still resistant to carbapenems after elimination of blaNDM and could be inhibited by PAβN. However, ST78(CY-9) lost its resistance to carbapenems. Knockout of asmA reduced the MIC of ST2260 by 16-fold. ST78 showed no such changes. Growth curves revealed impaired growth only in ST2260ΔasmA. Transcriptomics/qRT-PCR revealed no significantly altered acrAB-tolC or marA expression in either strain. Membrane proteomics detected AcrB loss specifically in ST2260ΔasmA. The loss of asmA affected a wide range of membrane proteins, especially OmpW. Molecular docking predicted that AsmA could bind to AcrB, with stronger binding energy in ST78. The buried area of the CY-8 model involved 110 contact residues, while the number of contacts of the CY-9 model increased to 144. The AsmA chain of the two models had 46 common contact residues, and the AcrB chain had 60 common contact residues. AcrB of ST78 generally carries the I277V mutation. Conclusion: asmA is highly conserved in Enterobacter cloacae. It has functional heterogeneity in different ST types. In ST2260, asmA can affect efflux pump-mediated carbapenem resistance. AsmA can regulate AcrAB-TolC not by affecting marA. It is predicted that AsmA can maintain the carbapenem resistance of Enterobacter cloacae ST2260 by helping AcrB anchor to the inner membrane. The difference in carbapenem resistance mediated by efflux pumps between ST78 and ST2260 suggests that ST78 commonly carries the AcrB I277V mutation, which is a key site for efflux of β-lactams.
2025-08-08 | GSE304310 | GEO