Ontology highlight
ABSTRACT:
PROVIDER: PRJNA508406 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| Other | ||||
| SRR8289540_1.fastq.gz | Fastqsanger.gz | |||
| SRR8289540_2.fastq.gz | Fastqsanger.gz | |||
| SRR8289550_1.fastq.gz | Fastqsanger.gz | |||
| SRR8289550_2.fastq.gz | Fastqsanger.gz |
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Project description:WGS of Carbapenem-resistant Gram-negative clinical isolates from Mali
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Project description:Background: It remains unclear how high-risk Escherichia coli lineages, like sequence type (ST) 131, initially adapt to carbapenem exposure in its progression to becoming carbapenem resistant. Methods: Carbapenem mutation frequency was measured in multiple subclades of extended-spectrum β-lactamase (ESBL) positive ST131 clinical isolates using a fluctuation assay followed by whole genome sequencing (WGS) characterization. Genomic, transcriptomic, and porin analyses of ST131 C2/H30Rx isolate, MB1860, under prolonged, increasing carbapenem exposure was performed using two distinct experimental evolutionary platforms to measure fast vs. slow adaptation. Results: All thirteen ESBL positive ST131 strains selected from a diverse (n=184) ST131 bacteremia cohort had detectable ertapenem (ETP) mutational frequencies with a statistically positive correlation between initial ESBL gene copy number and mutation frequency (r = 0.87, P<1e-5). WGS analysis of mutants showed initial response to ETP exposure resulted in significant increases in ESBL gene copy numbers or mutations in outer membrane porin (Omp) encoding genes in the absence of ESBL gene amplification with subclade specific adaptations. In both experimental evolutionary platforms, MB1860 responded to initial ETP exposure by increasing blaCTX-M-15 copy numbers via modular, insertion sequence 26 (IS26) mediated pseudocompound transposons (PCTns). Transposase activity driven by PCTn upregulation was a conserved expression signal in both experimental evolutionary platforms. Stable mutations in Omp encoding genes were detected only after prolonged increasing carbapenem exposure consistent with clinical observations. Conclusions: ESBL gene amplification is a conserved response to initial carbapenem exposure, especially within the high-risk ST131 C2 subclade. Targeting such amplification could assist with mitigating carbapenem resistance development.
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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.
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Project description:There is an urgent need for novel antibiotics against carbapenem and 3rd generation cephalosporin-resistant Gram-negative pathogens, for which the last-resort antibiotics have lost most of their efficacy. We describe here a novel class of synthetic antibiotics that was inspired from natural product-derived scaffolds. The antibiotics have an unprecedented mechanism of action, which targets the main component (BamA) of the Bam folding machinery required for folding and insertion of ß-barrel proteins into the outer membrane of Gram-negative bacteria. This OMPTA (outer membrane protein-targeting antibiotic) class shows potent activity against multidrug-resistant Gram-negative ESKAPE pathogens and overcomes colistin-resistance both in vitro and in vivo. A clinical candidate has the potential to address life threatening Gram-negative infections with high unmet medical need.
2019-10-22 | PXD010174 | Pride
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 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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