Physiology of Pseudomonas aeruginosa cells without major RND-type multidrug efflux pumps
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ABSTRACT:
PROVIDER: PRJNA714944 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR31841700_1.fastq.gz | Fastqsanger.gz | |||
| SRR31841700_2.fastq.gz | Fastqsanger.gz | |||
| SRR31841701_1.fastq.gz | Fastqsanger.gz | |||
| SRR31841701_2.fastq.gz | Fastqsanger.gz | |||
| SRR31841702_1.fastq.gz | Fastqsanger.gz |
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Project description:Purpose: In this study, we analyzed how P. aeruginosa physiology is adapted to the lack of RND-mediated efflux activities. Methods: In this study, we use PΔ6 cells to analyze how P. aeruginosa changes its physiology in response to the lack of efflux pumps and increased permeability of the cell envelope. We compared the transcriptomes of the exponentially growing and stationary PΔ6 and its parent PAO1 cells and identified the cellular functions stressed by the lack of active efflux. High quality total RNA was further processed by removing 23S and 16S rRNAs using the Illumina Ribo-Zero Plus rRNA Depletion kit. Samples were analyzed in duplicate using Illumina MiSeq. Raw data for each sample was analyzed using CLC Genomics Workbench version 12.0.1 software (QIAGEN Aarhus, Denmark). Results: P. aeruginosa PΔ6 strain lacking six best characterized RND pumps activates a specific adaptation response that involves significant changes in expression of specific subset of genes encoding e.g. several transport systems, quorum sensing or iron acquisition. Conclusion: Our results suggest that all changes we observe serve to protect the cell envelope of efflux-deficient P. aeruginosa.
2021-04-30 | GSE169036 | GEO
Project description:Pseudomonas aeruginosa is an opportunistic human pathogen, which is ubiquitous in the environment. The environmental versatility of P. aeruginosa is often attributed to a large arsenal of active efflux pumps, low permeability of the outer membrane and extensive regulatory networks. In this study, we analyzed putative functional interplay between polyspecific drug efflux pumps of Resistance-Nodulation-Division (RND) superfamily of proteins and GacSA two-component regulatory system. RND transporters are the major contributors to antibiotic resistance and survival under various environmental stresses, whereas GacSA is a global regulator and governs critical lifestyles during human colonization. We found that the inactivation of either RND pumps or gacS induces broad, partially overlapping responses in lifestyle, virulence and metabolic programs that are more pronounced during exponential than stationary phase. GacSA and RND efflux pumps induced opposite responses in gene expression of P. aeruginosa, whereas the overexpression of GacS was additive with the deletion of efflux pumps in gene expression and under growth conditions typically associated with human infections such as elevated temperature and iron deprivation. We conclude that RND efflux and GacSA networks partially overlap with each other.
2025-03-01 | GSE284138 | GEO
Project description:The number and overlapping substrate repertoire of multidrug efflux pumps in the E. coli genome suggest a physiological role apart from multidrug resistance. This role was investigated using transcriptomic analyses of cDNAs labeled from E. coli AG102 mRNA (hyper drug resistant, marR1) and its isogenic major efflux pump mutants. Keywords: Mutation Analysis
2008-03-11 | GSE10757 | GEO
Project description:Efflux pumps of the resistance-nodulation-division (RND) superfamily, particularly the AcrAB-TolC and MexAB-OprM, besides mediating intrinsic and acquired resistance, also intervene in bacterial pathogenicity. Inhibitors of such pumps could restore activities of antibiotics and curb bacterial virulence. Here, we identify pyrrole-based compounds that boost antibiotic activity in Escherichia coli and Pseudomonas aeruginosa by inhibiting their archetype RND transporters. The discovered efflux pump inhibitors (EPIs) inhibit the efflux of fluorescent probes, attenuate persister formation, and diminish resistant mutant development. Molecular docking and biophysical studies revealed that the EPIs bind to AcrB. EPIs also possess an anti-pathogenic potential and attenuate P. aeruginosa virulence in vivo. The excellent efficacy of the EPI-antibiotic combination was evidenced in animal lung infection and sepsis protection models. These findings indicate that EPIs discovered herein with no off-target effects and negligible toxicity are potential antibiotic adjuvants to address life-threatening bacterial infections.
2024-03-18 | GSE210309 | GEO
Project description:Functional interplay between RND efflux pumps and GacS in Pseudomonas aeruginosa
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Project description:Pyrrole-based inhibitors of RND-type efflux pumps reverse antibiotic resistance and display antivirulence potential
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Project description:RND (Resistance-Nodulation-Division) family transporters are widespread especially among Gram-negative bacteria, and catalyze the active efflux of many antibiotics and chemotherapeutic agents. They have very large periplasmic domains, and form tripartite complexes with outer membrane channels and periplasmic adaptor proteins. AcrAB-TolC complex of Escherichia coli, which pumps out a very wide range of drugs, has been studied most intensively. Early studies showed that the transporter captures even those substrates that cannot permeate across the cytoplasmic membrane, such as dianionic beta-lactams, suggesting that the capture can occur from the periplasm. It was also suggested that the capture occurs from the cytoplasmic membrane/periplasm interface, because most substrates contain a sizable hydrophobic domain; however, this may simply be a reflection of the nature of the binding site within AcrB. Genetic studies of chimeric transporters showed that much of the substrate specificity is determined by their periplasmic domains. Biochemical studies with intact cells recently led to the determination of the kinetic constants of AcrB for some beta-lactams, and the result confirms the old prediction that AcrB is a rather slow pump. Reconstitution of purified AcrB and its relatives showed that the pump is a drug/proton antiporter, that AcrA strongly stimulates the activity of the pump, and that AcrB seems to have a highest affinity for conjugated bile salts. Structural study with mutants of the network of charged residues in the transmembrane domain showed that protonation here produced a far-reaching conformational change, which was found to be present in one of the protomers in the asymmetric crystal structure of the wild-type AcrB. The functional rotatory hypothesis then predicts that the drug bound in the periplasmic domain is extruded through this conformational change initiated by the protonation of one of the residues in the aforementioned network, an idea that was recently supported by disulfide cross-linking as well as by the behavior of linked AcrB protomers.
| S-EPMC2696896 | biostudies-literature
Project description:Tripartite multidrug efflux systems of Gram-negative bacteria are composed of an inner membrane transporter, an outer membrane channel and a periplasmic adaptor protein. They are assumed to form ducts inside the periplasm facilitating drug exit across the outer membrane. Here we present the reconstitution of native Pseudomonas aeruginosa MexAB-OprM and Escherichia coli AcrAB-TolC tripartite Resistance Nodulation and cell Division (RND) efflux systems in a lipid nanodisc system. Single-particle analysis by electron microscopy reveals the inner and outer membrane protein components linked together via the periplasmic adaptor protein. This intrinsic ability of the native components to self-assemble also leads to the formation of a stable interspecies AcrA-MexB-TolC complex suggesting a common mechanism of tripartite assembly. Projection structures of all three complexes emphasize the role of the periplasmic adaptor protein as part of the exit duct with no physical interaction between the inner and outer membrane components.
| S-EPMC4754349 | biostudies-literature
Project description:To compare the expression profile of B. cenocepacia mutants impaired in RND efflux pump encoding genes
2011-04-23 | E-MEXP-2999 | biostudies-arrayexpress
Project description:Antibiotic resistance continues to rise as a global health threat. Novel anti-virulence strategies diminish the drive for evolutionary pressure, but still hinder a pathogen’s ability to infect a host. Treatment of the highly virulent Pseudomonas aeruginosa strain PA14 with virulence inhibitors (R-2 and R-6) elicited widely varying transcriptional profiles. Of interest, expression of a family of resistance-nodulation-division (RND) efflux pumps implicated in the intrinsic drug resistance of P. aeruginosa, was significantly altered by R-2 and R-6 treatment. While structurally similar, these inhibitors caused differential expression of various RND efflux pumps within the Mex family—R-2 treatment stimulated expression of mexEF-oprN while R-6 treatment led to increased mexAB-oprM expression. Further expansion into a small library of virulence inhibitors revealed chemical motifs that trigger increases in RND efflux pump expression. Additionally, activation of these efflux pumps suggests low accumulation of virulence inhibitors in WT PA14. Treatment of an efflux pump-deficient strain with R-2 or R-6 resulted in inhibition of several virulence factors, for example R-2 was found to abolish swimming motility. Collectively, treatment with either R-2 or R-6 gives rise to a convoluted transcriptomic response, confounded by the impact of efflux pump expression on the system. However, understanding the moieties that lead to high expression of the efflux pumps enables further rational design of novel virulence inhibitors that do not cause RND efflux pump activation.
2025-08-13 | GSE291940 | GEO