Ontology highlight
ABSTRACT:
PROVIDER: PRJNA932143 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR23354878_1.fastq.gz | Fastqsanger.gz |
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Project description:With the global increase in the use of carbapenems, several gram-negative bacteria have acquired carbapenem resistance, thereby limiting treatment options. Klebsiella pneumoniae is one of such notorious pathogen that is being widely studied to find novel resistance mechanisms and drug targets. These antibiotic-resistant clinical isolates generally harbor many genetic alterations, and identification of causal mutations will provide insights into the molecular mechanisms of antibiotic resistance. We propose a method to prioritize mutated genes responsible for antibiotic resistance, in which mutated genes that also show significant expression changes among their functionally coupled genes become more likely candidates. For network-based analyses, we developed a genome-scale co-functional network of K. pneumoniae genes, KlebNet (www.inetbio.org/klebnet). Using KlebNet, we could reconstruct functional modules for antibiotic-resistance, and virulence, and retrieved functional association between them. With complementation assays with top candidate genes, we could validate a gene for negative regulation of meropenem resistance and four genes for positive regulation of virulence in Galleria mellonella larvae. Therefore, our study demonstrated the feasibility of network-based identification of genes required for antimicrobial resistance and virulence of human pathogenic bacteria with genomic and transcriptomic profiles from antibiotic-resistant clinical isolates.
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Project description:The emergence and spread of polymyxin resistance, especially among Klebsiella pneumoniae isolates threaten the effective management of infections. This study profiled for polymyxin resistance mechanisms and investigated the activity of polymyxins plus vancomycin against carbapenem- and polymyxin-resistant K. pneumoniae.
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Project description:The increasing antibiotic resistance of Klebsiella pneumoniae poses a serious threat to global public health. To investigate the antibiotic resistance mechanism of Klebsiella pneumonia, we performed gene expression profiling analysis using RNA-seq data for clinical isolates of Klebsiella pneumonia, KPN16 and ATCC13883. Our results showed that mutant strain KPN16 is likely to act against the antibiotics through increased increased butanoate metabolism and lipopolysaccharide biosynthesis, and decreased transmembrane transport activity.
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Project description:Antibiotic use can lead to expansion of multi-drug resistant pathobionts within the gut microbiome that can cause life-threatening infections. Selective alternatives to conventional antibiotics are in dire need. Here, we describe a Klebsiella PhageBank that enables the rapid design of antimicrobial bacteriophage cocktails to treat multi-drug resistant Klebsiella pneumoniae. Using a transposon library in carbapenem-resistant K. pneumoniae, we identified host factors required for phage infection in major Klebsiella phage families. Leveraging the diversity of the PhageBank and experimental evolution strategies, we formulated combinations of phages that minimize the occurrence of phage resistance in vitro. Optimized bacteriophage cocktails selectively suppressed the burden of multi-drug resistant K. pneumoniae in the mouse gut microbiome and drove bacterial populations to lose key virulence factors that act as phage receptors. Further, phage-mediated diversification of bacterial populations in the gut enabled co-evolution of phage variants with higher virulence and a broader host range. Altogether, the Klebsiella PhageBank represents a roadmap for both phage researchers and clinicians to enable phage therapy against a critical multidrug-resistant human pathogen.
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Project description:The study aimed to characterize plasmids mediating carbepenem resistance in Klebsiella pneumoniae in Pretoria, South Africa. We analysed 56 K. pneumoniae isolates collected from academic hospital around Pretoria. Based on phenotypic and molecular results of these isolates, 6 representative isolates were chosen for further analysis using long reads sequencing platform. We observed multidrug resistant phenotype in all these isolates, including resistance to aminoglycosides, tetracycline, phenicol, fosfomycin, floroquinolones, and beta-lactams antibiotics. The blaOXA-48/181 and blaNDM-1/7 were manily the plasmid-mediated carbapenemases responsible for carbapenem resistance in the K. pneumoniae isolates in these academic hospitals. These carbapenemase genes were mainly associated with plasmid replicon groups IncF, IncL/M, IncA/C, and IncX3. This study showed plasmid-mediated carbapenemase spread of blaOXA and blaNDM genes mediated by conjugative plasmids in Pretoria hospitals.
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Project description:In this study, we introduce BacDrop, a bacterial droplet-based high throughput scRNA-seq technology that can be applied to large cell numbers. We applied BacDrop to study Klebsiella pneumoniae clinical isolates and elucidated their critical, genome-wide heterogeneity in the absence and presence of antibiotic perturbations.
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Project description:Antimicrobial resistance (AMR) is a pandemic spread across multiple infectious disease microbes. To provide a new tool to study AMR, here we develop a Klebsiella pneumoniae cell-free gene expression (CFE) system. To characterise the system, we use proteomics to compare this to a Escherichia coli MG1655 CFE model, to identify relative differences and unique proteins. Then we use this native CFE system to profile antimicrobial activity in comparison to whole cell inhibition, to reveal host differences in IC50/MIC50 values. Finally, we use the CFE tool to study AMR variants, at a proof-of-concept level. As an exemplar, we show that RpoB H526L confers a 58-fold increase in CFE resistance to rifampicin – a common genotype frequently observed in rifampicin-resistant Mycobacterium tuberculosis clinical isolates. In summary, we provide a cell-free synthetic biology strategy for the profiling of antibiotic sensitivity and resistance from K. pneumoniae. While initial processing requires Biosafety Level 2, the final extracts are non-living and suitable for long-term storage, and potentially transfer to a Biosafety Level 1 lab. This bioassay has potential uses for early-stage host-specific antimicrobial development and the testing of AMR variants for structure-activity relationship studies. The data reposited is label-free high-resolution LC-MS proteomics data performed to characterise the proteins in cell-free extract of K. pneumoniae ATCC 13882 and compare to that of E. coli MG1655 to identify common and unique proteins. We also characterised the proteins of K. pneumoniae clinically resistant isolates ST258-T1b and NJST258-1, and compared them to K. pneumoniae ATCC 13882 laboratory strain.
2023-11-29 | PXD046861 | Pride
Project description:Antimicrobial resistance (AMR) is a pandemic spread across multiple infectious disease microbes. To provide a new tool to study AMR, here we develop a Klebsiella pneumoniae cell-free gene expression (CFE) system. To characterise the system, we use proteomics to compare this to a Escherichia coli MG1655 CFE model, to identify relative differences and unique proteins. Then we use this native CFE system to profile antimicrobial activity in comparison to whole cell inhibition, to reveal host differences in IC50/MIC50 values. Finally, we use the CFE tool to study AMR variants, at a proof-of-concept level. As an exemplar, we show that RpoB H526L confers a 58-fold increase in CFE resistance to rifampicin – a common genotype frequently observed in rifampicin-resistant Mycobacterium tuberculosis clinical isolates. In summary, we provide a cell-free synthetic biology strategy for the profiling of antibiotic sensitivity and resistance from K. pneumoniae. While initial processing requires Biosafety Level 2, the final extracts are non-living and suitable for long-term storage, and potentially transfer to a Biosafety Level 1 lab. This bioassay has potential uses for early-stage host-specific antimicrobial development and the testing of AMR variants for structure-activity relationship studies. The data reposited is label-free high-resolution LC-MS proteomics data performed to characterise the proteins in cell-free extract of K. pneumoniae ATCC 13882 and compare to that of E. coli MG1655 to identify common and unique proteins. We also characterised the proteins of K. pneumoniae clinically resistant isolates ST258-T1b and NJST258-1, and compared them to K. pneumoniae ATCC 13882 laboratory strain.
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Project description:Antimicrobial resistance (AMR) arises from complex genetic and regulatory changes, including single mutations, gene acquisitions or cumulative effects. Advancements in genomics and proteomics facilitate more comprehensive understanding of the mechanisms behind antimicrobial resistance. In this study, 74 clinically obtained Klebsiella pneumoniae isolates with increased meropenem and/or imipenem MICs were characterized by broth microdilution and PCR to check for the presence of carbapenemase genes. Subsequently, a representative subset of 15 isolates was selected for whole genome sequencing (WGS) by Illumina and Nanopore sequencing, and proteomic analysis by liquid chromatography-mass spectrometry (LC-MS/MS) to investigate the mechanisms underlying the differences in carbapenem susceptibility of Klebsiella pneumoniae isolates. Identical techniques were applied to characterize 4 mutants obtained after sequential meropenem exposure. We demonstrated that in clinically obtained isolates, increased copy numbers of blaOXA-48 containing plasmids, combined with OmpK36 loss, contributed to high carbapenem MICs without involvement of OmpK35 or other porins or efflux systems. In the meropenem exposed mutants, increased copy numbers of blaCTX-M-15 or blaOXA-48 containing plasmids, combined with OmpK36 loss was demonstrated. The OmpK36 loss resulted from the insertion of IS1 transposable elements or partial deletion of the ompK36 gene. Additionally, we identified two mutations, C59A and C58A, in the DNA coding the copA antisense RNA of IncFII plasmids and multiple mutations of an IncR plasmid, associated with increased plasmid copy numbers. This study demonstrates that by combining WGS and LC-MS/MS, the effect of genomic changes on protein expression related to antibiotic resistance and the mechanisms behind antibiotic resistance can be elucidated.
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Project description:Shotgun Proteomic Analysis of ESBL and non ESBL Producing Klebsiella Pneumoniae Clinical Isolates
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