Ontology highlight
ABSTRACT:
PROVIDER: PRJNA557813 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| Other | ||||
| SRR10160924_1.fastq.gz | Fastqsanger.gz | |||
| SRR10160924_2.fastq.gz | Fastqsanger.gz | |||
| SRR10160925_1.fastq.gz | Fastqsanger.gz | |||
| SRR10160925_2.fastq.gz | Fastqsanger.gz |
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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: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:Klebsiella pneumoniae is an important human pathogen, causing various infections. Apart from traditional virulence factors, there remains a significant gap in the discovery and research of new chromosomal virulence factors. CpxR is a two-component system (TCS) response regulator, but its impact on the virulence of Klebsiella pneumoniae have not been conclusively determined. For the effect of CpxR on K. pneumoniae virulence, the cpxR deletion(ΔcpxR) strain exhibited reduced serum resistance and attenuated pathogenicity in both Galleria mellonella larvae and mouse infection models compared to the wild-type strain. To identify CpxR-regulated virulence genes, RNA-seq analysis was conducted, followed by deletion of transcription downregulated genes in the ΔcpxR strain. Through serum resistance assays and Galleria mellonella infection experiments, a novel potential virulence factor, KPHS_28080, was identified. Deletion of KPHS_28080 impaired serum survival and proliferation in carbapenem-resistant strains HS11286 and hypervirulent strain ATCC 43816. Furthermore, the ATCC 43816 ΔKPHS_28080 strain showed significantly reduced colonization, proliferation, and multi-organ dissemination capacity in mice, accompanied by diminished pathogenicity. The KPHS_28080 promoter contains a conserved CpxR binding motif, where CpxR binding enhances promoter activity and elevates gene transcription. Sequence alignment revealed that KPHS_28080 is widely conserved across Klebsiella pneumoniae strains, establishing it as a novel chromosome-encoded virulence factor. These results provide a new insight into the CpxR regulation of K. pneumoniae virulence and chromosomal virulence factors.
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Project description:Proteomic analysis of carbapenem-resistant Klebsiella pneumoniae exposure to tigecycline and aminoglycosides
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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:WGS of Carbapenem-resistant Klebsiella pneumoniae (CRKp) from Singapore and USA
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Project description:Carbapenem-resistant Klebsiella pneumoniae (CRKP) poses a major global health threat, particularly in healthcare-associated infections. While carbapenemase- and porin-centered mechanisms are well characterized, how subinhibitory carbapenem exposure selects noncanonical adaptive routes remains unclear. Here, we show that subinhibitory meropenem promotes O_x001E_antigen loss in K. pneumoniae, predominantly mediated by insertion sequences (IS), thereby enhancing carbapenem resistance. O_x001E_antigen deficiency rewires metabolism under meropenem pressure, especially glycine, serine, and threonine pathways, dampening reactive oxygen species (ROS) accumulation and limiting oxidative killing; exogenous glycine restores ROS production and meropenem susceptibility. Genomic surveys reveal widespread O_x001E_antigen loss in K. pneumoniae, largely driven by IS, and also in Escherichia coli, and O_x001E_antigen–deficient mutants confirm its role in promoting carbapenem resistance. Importantly, this adaptation entails a trade-off: it improves survival under carbapenem pressure but increases serum susceptibility, destabilizes the capsule, attenuates virulence in murine infection models, and confers collateral sensitivity to aminoglycosides. These findings uncover a previously unrecognized route to carbapenem resistance that links O_x001E_antigen remodeling to metabolic rewiring, offering conceptual and therapeutic leverage points.
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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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