Ontology highlight
ABSTRACT:
PROVIDER: PRJNA836848 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR19154344_1.fastq.gz | Fastqsanger.gz | |||
| SRR19154344_2.fastq.gz | Fastqsanger.gz |
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Project description:Objectives: Carbapenem-resistant Acinetobacter baumannii (CRAB) are one of the most difficult pathogen to treat. The only drug recently approved by the FDA that is active against CRAB is cefiderocol. However, recent studies have shown higher all-cause mortality rate in the group of patients treated with cefiderocol, that may be due to heteroresistance, a phenotype characterized by the survival of a small proportion of cells in a population seemingly isogenic. Previous studies showed that adding human fluids to CRAB cultures can lead to CFDC heteroresistance. To better understand the nature of this phenomenon, we carried out molecular and phenotypic analyses of CRAB heteroresistant bacterial subpopulations. Methods: The CRAB strain AMA40 was cultured in the presence of cefiderocol and human pleural fluid (HPF) to isolate heteroresistant variants. Two of them, AMA40 IHC_1 and IHC_2, were subjected to whole genome sequencing and transcriptomic analysis to identify the mutations and transcriptomic changes responsible for the development of cefiderocol resistance. The impact of mutations on the pharmacodynamic activity of cefiderocol was assessed by susceptibility testing, EDTA and Boronic acid inhibition analysis, biofilm formation, and static time-kill assays. Results: Variants AMA40 IHC_1 and IHC_2 had 53 mutations, forty of which were common to both heteroresistant strains. None of the mutations are located inside genes associated with iron-uptake systems or β-lactam resistance. However, pipA, a gene associated with iron homeostasis in other species, was mutated in heteroresistant strains. Transcriptomic analyses revealed modifications in levels of expression of genes associated with antibiotic resistance. The blaNDM-1, blaADC-2, pbp3, and pbp1 were expressed at higher levels. At the same time, the carO and ompA genes’ expression was reduced. Collateral resistance to amikacin was observed in the heteroresistant variants. Static time-kill assays showed that when CA-MHB was supplemented with human serum albumin, the main protein component of HPF, cefiderocol killing activity was considerably reduced in all three strains. Conclusions: We conclude that heteroresistance to cefiderocol in CRAB, when exposed to fluids containing high HSA, is caused by mutations and modifications in the expression of genes associated with resistance to β-lactams.
2023-03-31 | E-MTAB-12444 | biostudies-arrayexpress
Project description:Beta-Lactam Pan-Resistant NDM-Producing Escherichia Coli
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Project description:Methicillin-resistant Staphylococcus aureus (MRSA) poses a significant challenge to public health due to its evolving resistance to antibiotics. In addressing this concern, we employed a multi-omics approach, integrating proteomics and Transposon Directed Insertion-site Sequencing (TraDIS), to comprehensively investigate adaptive response of MRSA to β-lactam antibiotics and identify key genetic determinants influencing susceptibility. Proteomic analysis revealed significant shifts in the protein spectrum under sub-inhibitory concentrations of oxacillin and cefazolin, characterized by a stringent response. This included the upregulation of amino acid metabolism and oligopeptide transport pathways, along with the downregulation of arginine biosynthesis. Concurrent TraDIS screening identified 50 genes whose inactivation conferred a fitness advantage in the presence of both β-lactams, implicating processes such as nucleotide second messenger signaling, DNA repair, and histidine transport. Validation of selected mutants (relA::Tn, mutY::Tn, nsaR::Tn, aroC::Tn, SAUSA300_0432::Tn, SAUSA300_0846::Tn, SAUSA300_0595::Tn) confirmed these findings, demonstrating improved fitness in the presence of β-lactams. Integrative analysis of proteomic and TraDIS datasets highlighted the implication of the stringent response in mediating MRSA adaptation to β-lactams. These findings establish the 'susceptome' concept, a collection of genes that maintain or potentiate MRSA's vulnerability to β-lactams, providing new targets for therapeutic intervention and strategies to counteract resistance evolution.
2025-12-12 | PXD062516 | Pride
Project description:Acinetobacter baumannii causes high mortality in ventilator-associated pneumonia patients and antibiotic treatment is compromised in multi-drug resistant strains resistant to beta-lactams, carbapenems, cephalosporins, polymyxins and tetracyclines. Among COVID-19 patients receiving ventilator support, multi-drug resistant A. baumannii secondary infection is associated with a two-fold increase in mortality. Here we investigated the use of the 8-hydroxyquinoline ionophore PBT2 to break resistance of A. baumannii to tetracycline class antibiotics.
2021-12-17 | GSE175535 | GEO
Project description:Carbapenem-resistant Acinetobacter baumannii (CRAB) is a global health threat with few effective treatment options remaining. Cefiderocol, a last-resort siderophore-cephalosporin antibiotic, exploits bacterial iron transport systems via TonB-dependent receptors (TBDRs) to gain cellular entry. However, treatment failures and emerging resistance highlight the complexity of its activity in vivo. In this study, we report an unanticipated cefiderocol resistance mechanism, where vitamin B12, a commonly used micronutrient supplement, modulates cefiderocol susceptibility. Vitamin B12 affect and interact with TBDRs and other metabolic and adaptation processes contributing to increases cefiderocol MIC level and emergence of persistence phenotypes. We show that vitamin B12 supplementations leads to strain-specific transcriptomic responses in the CRAB AB5075 and AMA17 strains, showing downregulation of siderophore transporters, stress responses, metabolic reprogramming, and biofilm-associated genes. Structural modeling and molecular docking reveal overlapping binding sites for vitamin B12 and cefiderocol within key TBDRs such as CirA and PirA, suggesting competitive inhibition. Additionally, vitamin B12 exposure increases cefiderocol MICs across a panel of clinical and reference strains, enhances survival in time-kill assays, and promotes emergence of small colony variants with persistent phenotypes. Notably, this effect is stable, dose-dependent and further seen to be increased in the presence of host-derived fluids. These findings describe a previously unrecognized host–pathogen–drug interaction with potential clinical implications, suggesting that vitamin B12 exposure could contribute to cefiderocol treatment failure. Our results underscore the urgent need to consider vitamin supplements potential contribution in antimicrobial therapy and CRAB management strategies.
2026-01-01 | GSE307121 | GEO