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Escherichia coli BW25113

ABSTRACT: Elucidating TolC Protein Dynamics Structural Shifts Facilitate Efflux Mediated Beta-Lactam Resistance

PROVIDER: PRJNA1078904 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR28040027_1.fastq.gz	Fastqsanger.gz
	SRR28040027_2.fastq.gz	Fastqsanger.gz
	SRR28040028_1.fastq.gz	Fastqsanger.gz
	SRR28040028_2.fastq.gz	Fastqsanger.gz
	SRR28040029_1.fastq.gz	Fastqsanger.gz

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Escherichia coli BW25113

Project description:Escherichia coli beta-lactam TraDIS

| PRJNA875263 | ENA

Conformational restriction shapes the inhibition of a multidrug efflux adaptor protein

Project description:Membrane efflux pumps play a major role in bacterial multidrug resistance. The tripartite multidrug efflux pump system from Escherichia coli, AcrAB-TolC, is a target for inhibition to lessen resistance development and restore antibiotic efficacy, with homologs in other ESKAPE pathogens. Here, we rationalize a mechanism of inhibition against the periplasmic adaptor protein, AcrA, using a combination of hydrogen/deuterium exchange mass spectrometry, cellular efflux assays, and molecular dynamics simulations. We define the structural dynamics of AcrA and find that an inhibitor can inflict long-range stabilisation across all four of its domains, whereas an interacting efflux substrate has minimal effect. Our results support a model where an inhibitor forms a molecular wedge within a cleft between the lipoyl and αβ domains of AcrA, diminishing its conformational transmission of drug-evoked signals from AcrB to TolC. This work provides molecular insights into multidrug adaptor protein function which could be valuable for developing antimicrobial therapeutics.

2023-06-01 | PXD041359 | Pride

A TetR-family regulator of an RND efflux system that directs artemisinin resistance in Vibrio cholerae

Project description:Artemisinin (ARS) displayed bactericidal activity against Vibrio cholerae. To assess the mechanistic details of its antibacterial action, we have isolated V. cholerae mutants with enhanced ARS resistance and identified a gene (VCA0767), whose loss-of-function resulted in the ARS resistance phenotypes. This gene (atrR) encodes a TetR family transcriptional regulator, and its deletion mutant displayed the reduction in ARS-induced ROS formation and DNA damage. Transcriptomic analysis revealed that the genes encoding an RND efflux pump operon (vexRAB) and the outer membrane component (tolC) were highly upregulated in the artR mutant, suggesting that AtrR might act as a negative regulator of this operon and tolC. Gene deletion of vexR, vexB or tolC abrogated the ARS resistance of the atrR mutant and, more importantly, the ectopic expression of VexAB-TolC was sufficient for the ARS resistance, indicating that the increased expression of the VexAB-TolC efflux system is necessary and sufficient for the ARS resistance of the atrR mutant. The cytoplasmic accumulation of ARS was compromised in the vexBtolC mutant, suggesting that the VexAB-TolC might be the primary efflux system exporting ARS to reduce its toxicity inside of the bacterial cells. The atrR mutant displayed resistance to erythromycin as well in a VexR-dependent manner. This result suggests that AtrR may act as a global regulator responsible for preventing intracellular accumulation of toxic chemicals by enhancing the RND efflux system.

2023-10-16 | GSE245142 | GEO

Genome wide analysis of genes involved in efflux function and regulation within Escherichia coli and Salmonella enterica serovar Typhimurium

Project description:Expression of efflux pumps is a key feature of most cells which are resistant to multiple antibiotics. This study used TraDIS-Xpress, a genome wide transposon mutagenesis technology to identify genes in Escherichia coli and Salmonella Typhimurium involved in drug efflux and its regulation. We exposed mutant libraries to the canonical efflux substrate acriflavine in the presence and absence of the efflux inhibitor phenylalanine-arginine β-naphthylamide. Comparisons between conditions identified efflux specific and drug specific responses. Known efflux associated genes were easily identified including: AcrAB-TolC, MarA, RamA and SoxS confirming specificity of the response. Further genes encoding cell envelope maintenance enzymes and products involved with stringent response activation, DNA housekeeping, respiration and glutathione biosynthesis were also identified as affecting efflux activity in both species. We identified a conserved set of pathways crucial for efflux activity in these experimental conditions which expands the list of genes known to impact efflux efficacy.

2022-11-12 | E-MTAB-12353 | biostudies-arrayexpress

Real-time visualization of drug resistance acquisition by horizontal gene transfer reveals a new role for AcrAB-TolC multidrug efflux pump

Project description:In our study, we obtained evidence showing that, in the presence of tetracycline, AcrAB-TolC multidrug efflux pump was required for production of protein encoded by a conjugative plasmid acquired by bacterial conjugation. We then address the role of AcrAB-TolC multidrug efflux pump on the level of protein synthesis activity in the presence of tetracycline, which inhibits protein translation by targeting ribosomal 16S rRNA and competing with binding of the anticodon-stem loop of an A-site tRNA. We used a quantitative TMT-nanoLC-mass spectrometry approach to obtained the protein relative abundance ratio before and after incubation with tetracycline, and so in wild-type(MG1655, K12) and AcrAB-TolC mutant strains (ΔacrA, ΔacrB and ΔtolC).

2019-07-16 | PXD011286 | Pride

Expression data of the acrR mutant E.coli compared to wild-type

Project description:AcrR is a known transcriptional repressor for AcrAB-TolC multidrug efflux system and mar-sox regulators. We used microarrays to investigate genome-wide target genes for AcrR. In the acrR deletion mutant, the transcription of genes for flagella and motility are significantly increased, indicating that AcrR plays a role in motility of E. coli.

2016-07-27 | GSE84847 | GEO

A genetic platform to investigate the functions of bacterial drug efflux pumps

Project description:Efflux pumps are a significant challenge for the development of new antibacterial agents. Overcoming efflux requires an in-depth understanding of efflux pump functions, substrate specificities, and the development of inhibitors. However, the complexities of drug efflux networks have limited such studies. To address these challenges, we report the generation of Efflux KnockOut-35 (EKO-35), a highly susceptible Escherichia coli strain lacking 35 efflux pumps. We demonstrate the utility of this strain by constructing an efflux platform consisting of strains individually expressing genes encoding efflux pumps forming tripartite complexes with the outer membrane channel TolC. This platform was profiled against a curated diverse compound collection, which enabled us to define physicochemical properties that contribute to transport. We also show the E. coli drug efflux network is conditionally essential for growth, and that the platform can be used to investigate efflux pump inhibitor specificities and also efflux pump interplay. We believe EKO-35 and the efflux platform will have widespread application for the study of drug efflux.

2022-08-31 | PXD033975 | Pride

HDX-MS reveals the perturbed structural dynamics underlie inhibition and altered specificity of the multidrug efflux pump AcrB

Project description:Perturbed structural dynamics underlie inhibition and altered specificity of the multidrug efflux pump AcrB

2020-10-07 | PXD019047 | Pride

First penicillin-binding protein occupancy patterns for 15 β-lactams and β-lactamase inhibitors in Mycobacterium abscessus

Project description:Mycobacterium abscessus (Mab) causes serious infections that often require over 18 months of antibiotic combination therapy. With β lactam antibiotics being safe, double β-lactam and β-lactam/β-lactamase inhibitor combinations are of interest for improving treatment of Mab infections and minimizing toxicity. However, a mechanistic approach for building these combinations is lacking since little is known about which penicillin-binding protein (PBP) target receptors are inactivated by different β-lactams in Mab. This project aimed to identify PBPs in Mab and study the binding affinities of each of these PBPs with β-lactam antibiotics. These first PBP occupancy patterns in Mab provide a mechanistic foundation for selecting and optimizing safe and effective combination therapies with β-lactams.

2020-11-24 | PXD022644 | Pride

Project description:Adaptive Evolution of Strains with AcrAB-TolC Efflux Pumps to Chloramphenicol

| PRJNA666010 | ENA