Heteroresistance
Ontology highlight
ABSTRACT:
PROVIDER: PRJEB49056 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| Other | ||||
| ERR7803730.fastq.gz | Fastqsanger.gz | |||
| ERR7813760_1.fastq.gz | Fastqsanger.gz | |||
| ERR7813760_2.fastq.gz | Fastqsanger.gz | |||
| ERR7813770_1.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: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:Heteroresistance in bacteria describes a subpopulational phenomenon of transient antibiotic resistance variation among cells of a generally susceptible population. Here, we investigated the molecular mechanisms and phenotypic characteristics underlying heteroresistance to ceftazidime (CAZ) in a clinical Enterobacter cloacae complex strain (ECC). We identified a plasmid-borne gene duplication-amplification (GDA) event of a region harboring an ampC gene encoding a β-lactamase blaDHA-1 as the key determinant of heteroresistance. Individual colonies exhibited variations in the copy number of the genes resulting in resistance level variation which correlated with growth onset (lag times) and growth rates in the presence of CAZ, analysed in linear models. GDA copy number heterogeneity occurred within single resistant colonies, demonstrating heterogeneity of GDA on the single-cell level. The interdependence between GDA, lag time and antibiotic treatment and the strong plasticity underlying heteroresistance underlines the high risk for misdetection of antimicrobial heteroresistance and subsequent treatment failure.
2024-10-17 | PXD056728 | Pride
Project description:Nitrofurantoin heteroresistance in Escherichia coli
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Project description:Bedaquiline micro-heteroresistance after tuberculosis treatment cessation
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Project description:Klebsiella pneumoniae clinical isolates, OXA48 and Wt, colistin heteroresistance
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Project description:Enterobacter bugandensis is one of species from the E. cloacae complex (ECC) that has been predominantly associated to neonatal sepsis. A major concern with E. bugandensis and ECC bacteria in general is the frequent appearance of multidrug resistant isolates including those resistant to last-resort antibiotics, such as polymyxins, for which these microbes are in the ESKAPE list of global threat pathogens. Here, we investigated polymyxin B (PmB) resistance and heteroresistance in E. bugandensis by transcriptomics and a gene deletion approach using two clinical isolates. Genes encoded in the CrrAB-regulated operon including crrC and kexD were highly upregulated in both strains in the presence of PmB. We show in one of these isolates that ∆crrC and ∆kexD mutants exhibited lower levels of PmB resistance and heteroresistance than the parental strain. Moreover, the heterologous expression of CrrC and KexD proteins increased PmB resistance in a sensitive E. ludwigii clinical isolate and in the Escherichia coli K12 strain W3110. We also showed that the efflux pump AcrAB and TolC contribute to PmB resistance and heteroresistance. Deletion of the regulatory genes phoPQ and crrAB cause reduced PmB resistance and heteroresistance, while deletion of pmrAB did not have any effect. Our results also reveal that the addition of L-Ara4N into the lipid A, mediated by the arnBCADTEF operon, is critical to determine PmB resistance, while the deletion of eptA, encoding a PEtN transferase had no effect. Finally, PmB resistance did not correlate with pathogenicity in the Galleria mellonella infection model.
2024-04-05 | PXD042287 | Pride
Project description:Heteroresistance of ceftazidime-avibactam in KPC-Producing Klebsiella pneumoniae is mainly caused by the KPC-2 mutation
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Project description:Antibiotic resistance associated with the expression of the clinically significant carbapenemases, IMP, KPC, and NDM and OXA-48 in Enterobacteriaceae is emerging as a worldwide calamity to health care. In Australia, IMP-producing Enterobacteriaceae is the most prevalent carbapenemase-producing Enterobacteriaceae (CPE). Genomic characteristics of such carbapenemase-producing Enterobacteriaceae (CPE) are well described, but the corresponding proteome is poorly characterised. We have thus developed a method to analyse dynamic changes in the proteome of CPE under antibiotic pressure. Specifically, we have investigated the effect of meropenem at sub-lethal concentrations to develop a better understanding of how antibiotic pressure leads to resistance. Escherichia coli, producing either NDM, IMP or KPC type carbapenemase were included in this study, and their proteomes were analysed in growth conditions with or without meropenem.
2018-07-11 | PXD008019 | Pride