Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1207282 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR31915943_1.fastq.gz | Fastqsanger.gz | |||
| SRR31915943_2.fastq.gz | Fastqsanger.gz |
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Project description:Enterobacter cloacae is a Gram-negative nosocomial pathogen of the ESKAPE (Enterococcus, Staphylococcus, Klebsiella, Acinetobacter, Pseudomonas, and Enterobacter spp.) priority group with increasing multi-drug resistance via the acquisition of resistance plasmids. However, E. cloacae can also display forms of antibiotic refractoriness, such as heteroresistance and tolerance. Here, we report that E. cloacae displays transient heteroresistance to aminoglycosides, which is accompanied with the formation of small colony variants (SCVs) with increased minimum inhibitor concentration (MIC) of gentamicin and other aminoglycosides used in the clinic, but not other antibiotic classes. To explore the underlying mechanisms, we performed RNA sequencing of heteroresistant bacteria, which revealed global gene-expression changes and a signature of the CpxRA cell envelope stress response. Deletion of the cpxRA two-component system abrogated aminoglycoside heteroresistance and SCV formation, pointing to its indispensable role in these processes. The introduction of a constitutively active allele of cpxA led to high aminoglycoside MICs, consistent with cell envelope stress response driving these behaviours in E. cloacae. Cell envelope stress can be caused by environmental cues, including heavy metals. Indeed, bacterial exposure to copper increased gentamicin MIC in the wild-type, but not in the ΔcpxRA mutant. Moreover, copper exposure also elevated the gentamicin MICs of clinical isolates from bloodstream infections, suggesting that CpxRA- and copper-dependent aminoglycoside resistance is broadly conserved in E. cloacae strains. Altogether, we establish that E. cloacae relies on transcriptional reprogramming via the envelope stress response pathway for transient resistance to a major class of frontline antibiotic.
2023-10-18 | GSE236124 | GEO
Project description:The spread of antimicrobial resistance (AMR), coupled with the decline in antibiotic development, has become a major public health concern. Recent studies estimate that around 700,000 people die each year from infections caused by multidrug-resistant (MDR) bacteria. This led the WHO to publish the ESKAPEE list of high priority pathogens for AMR, namely Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter spp. and Escherichia coli. Among these, Gram-negative bacteria (K. pneumoniae, A. baumannii, P. aeruginosa, Enterobacter spp., and E. coli) are particularly overrepresented. This is mainly due to their high propensity to develop multiple resistance mechanisms, in addition to their intrinsic resistance to many antimicrobials, which is due to their membrane composition and the expression of broad-spectrum efflux pumps. One strategy to combat such AMR is the use of drug enhancers that are able to restore the antibacterial activity of poorly active antibiotics. In this context, we demonstrated that the polyamino-isoprenyl enhancer, NV716, efficiently potentiates the antibacterial activity of two families of multi-target Ser/Cys-based enzyme inhibitors, namely the oxadiazolone derivatives (OX) and the Cyclipostins and Cyclophostin analogs (CyC), against Enterobacter cloacae, while remaining inactive against other Gram-negative bacteria. We confirmed that NV716 potentiates some OX & CyC compounds by permeabilizing the outer membrane and thus by increasing the inhibitor accumulation as shown by fluorescence confocal microscopy. By using bio-orthogonal click-chemistry activity-based protein profiling (CC-ABPP) approach coupled to proteomic analysis, we also identified the target proteins of the best OX & CyC inhibitors from E. cloacae lysate, thereby confirming their multi-target nature. Interestingly, 6 of the latter proteins were also captured via CC-ABPP in P. aeruginosa lysate, and are highly conserved in all Gram-negative bacteria. These results provide proof of concept that both OX & CyC, if successfully potentiated, could be used against a wide range of ESKAPEE Gram-negative bacteria.
2025-02-27 | PXD052024 | Pride
Project description:The spread of antimicrobial resistance (AMR), coupled with the decline in antibiotic development, has become a major public health concern. Recent studies estimate that around 700,000 people die each year from infections caused by multidrug-resistant (MDR) bacteria. This led the WHO to publish the ESKAPEE list of high priority pathogens for AMR, namely Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter spp. and Escherichia coli. Among these, Gram-negative bacteria (K. pneumoniae, A. baumannii, P. aeruginosa, Enterobacter spp., and E. coli) are particularly overrepresented. This is mainly due to their high propensity to develop multiple resistance mechanisms, in addition to their intrinsic resistance to many antimicrobials, which is due to their membrane composition and the expression of broad-spectrum efflux pumps. One strategy to combat such AMR is the use of drug enhancers that are able to restore the antibacterial activity of poorly active antibiotics. In this context, we demonstrated that the polyamino-isoprenyl enhancer, NV716, efficiently potentiates the antibacterial activity of two families of multi-target Ser/Cys-based enzyme inhibitors, namely the oxadiazolone derivatives (OX) and the Cyclipostins and Cyclophostin analogs (CyC), against Enterobacter cloacae, while remaining inactive against other Gram-negative bacteria. We confirmed that NV716 potentiates some OX & CyC compounds by permeabilizing the outer membrane and thus by increasing the inhibitor accumulation as shown by fluorescence confocal microscopy. By using bio-orthogonal click-chemistry activity-based protein profiling (CC-ABPP) approach coupled to proteomic analysis, we also identified the target proteins of the best OX & CyC inhibitors from E. cloacae lysate, thereby confirming their multi-target nature. Interestingly, 6 of the latter proteins were also captured via CC-ABPP in P. aeruginosa lysate, and are highly conserved in all Gram-negative bacteria. These results provide proof of concept that both OX & CyC, if successfully potentiated, could be used against a wide range of ESKAPEE Gram-negative bacteria.
2025-02-27 | PXD053955 | Pride
Project description:Recently, we have reported on a highly drug-resistant carbapenemase-producing isolate of Enterobacter cloacae (Nepal et al., Virulence. 2018; 9: 1377-1389). In the present study, we asked the question whether and, if so, how this isolate responds to a sub-inhibitory challenge with the antibiotic imipenem. To answer this question, we applied a SILAC proteomics approach that allowed the quantification of changes in the relative abundance of bacterial protein in response to imipenem. The results show that the investigated E. cloacae isolate mounts a highly specific response to counteract the detrimental effects of imipenem.
2021-08-10 | PXD013412 | Pride
Project description:Background: Enterobacter cloacae complex (ECC) is a common opportunistic pathogen and is responsible for causing various infections in humans. Owing to its inducible chromosomal AmpC β-lactamase (AmpC), ECC is inherently resistant to the 1st- and 2nd- generation cephalosporins. However, whether β-lactams antibiotics enhance ECC resistance remains unclear. Results: In this study, we found that subinhibitory concentrations (SICs) of cefazolin (CFZ) and imipenem (IMP) can advance the expression of AmpC and enhance its resistance towards β-lactams through NagZ in Enterobacter cloacae (EC). Further, AmpC manifested a substantial upregulation in EC in response to SICs of CFZ and IMP. In nagZ knockout EC (ΔnagZ), the resistance to β-lactam antibiotics was rather weakened and the effect of CFZ and IMP on AmpC induction was completely abrogated. NagZ ectopic expression can rescue the induction effects of CFZ and IMP on AmpC and increase ΔnagZ resistance. More importantly, CFZ and IMP have the potential to induce the expression of AmpR's target genes in a NagZ-dependent manner. Conclusions: Our findings suggest that NagZ is a critical determinant for CFZ and IMP to promote AmpC expression and resistance and that CFZ and IMP should be used with caution since they may aggravate ECC resistance. At the same time, this study further improves our understanding of resistance mechanisms in ECC.
2022-07-01 | GSE207144 | GEO