Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1184772 | ENA |
REPOSITORIES: ENA
Similar Datasets
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: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
Project description:Antibiotic resistance is one of the most pressing threats to human health, yet recent work highlights how loss of resistance may also drive pathogenesis in some bacteria. In two recent studies, we found that in vitro beta-lactam antibiotic and nutrient stresses faced during infection selected for the genetic inactivation of the Pseudomonas aeruginosa (Pa) antibiotic efflux pump mexEFoprN. Unexpectedly, efflux pump mutations increased Pa virulence during infection; however, neither the prevalence of efflux pump inactivating mutations in real human infections, nor the mechanisms driving increased virulence of efflux pump mutants were known. We hypothesized that human infection would select for efflux pump mutations that drive increased virulence in Pa clinical isolates. Using genome sequencing of hundreds of Pa clinical isolates, we show that mexEFoprN efflux pump inactivating mutations are enriched in Pa cystic fibrosis isolates relative to Pa intensive care unit clinical isolates. Combining RNA-seq, metabolomics, genetic approaches, and infection models we show that efflux pump mutants increase expression of two key Pa virulence factors, elastase and rhamnolipids, which increased Pa virulence and lung damage during both acute and chronic infections. We show that increased virulence factor production was driven by increased Pseudomonas quinolone signal levels, and this mechanism of increased virulence held true in both a representative ICU clinical isolate and the notorious CF Pa Liverpool epidemic strain. Together, our findings suggest that mutations inactivating antibiotic resistance mechanisms could increase patient mortality and morbidity.
2024-11-12 | MSV000096391 | MassIVE
Project description:An antivirulence approach targets bacterial virulence rather than cell viability in the antibiotic approach that can readily lead to drug resistance. Opportunistic human pathogen Pseudomonas aeruginosa produces a variety of virulence factors, and biofilm cells of this bacterium are much more resistant to antibiotics than planktonic cells. To identify novel inorganic antivirulence compounds, the dual screenings of thirty-six metal ions were performed to identify that zinc ions and ZnO nanoparticle inhibited the pyocyanin production and biofilm formation in P. aeruginosa without affecting the growth of planktonic cells. Moreover, zinc ion and ZnO nanoparticle markedly reduced the production of 2-heptyl-3-hydroxy-4(1H)-quinolone and siderophore pyochelin, while increased the production of another sideropore pyoverdine and swarming motility. Further, zinc ion and ZnO nanoparticle clearly suppressed hemolytic activity in P. aeruginosa. Transcriptome analyses showed that ZnO nanoparticle induced zinc cation efflux pump czc operon, porin genes (oprD and opdT), and Pseudomonas type III repressor A ptrA, while repressed pyocyanin-related phz operon, which partially explains the phenotypic changes. Overall, ZnO nanoparticle is a potential candidate for use in an antivirulence approach against persistent P. aeruginosa infection.
2015-05-25 | GSE46947 | GEO
Project description:Multidrug (MDR) efflux pumps are ancient and conserved molecular machineries with relevant roles in different aspects of the bacterial physiology, besides antibiotic resistance. In the case of the environmental opportunistic pathogen Pseudomonas aeruginosa, it has been shown that overexpression of different efflux pumps is linked to the impairment of the quorum sensing (QS) response. Nevertheless, the causes of such impairment are different for each analyzed efflux pump. Herein, we performed an in-depth analysis of the QS-mediated response of a P. aeruginosa antibiotic resistant mutant that overexpresses MexAB-OprM. Although previous work claimed that this efflux pump extrudes the QS signal 3-oxo-C12-HSL, we show otherwise. Our results evidence that the observed attenuation in the QS response when overexpressing this pump is related to an impaired production of alkyl quinolone QS signals, likely prompted by the reduced availability of one of their precursors, the octanoate. Together with previous studies, this indicates that, although the consequences of overexpressing efflux pumps are similar (impaired QS response), the underlying mechanisms are different. This ‘apparent redundancy' of MDR efflux systems can be understood as a P. aeruginosa strategy to keep the robustness of the QS regulatory network and modulate its output in response to different signals.
2021-10-25 | GSE153996 | GEO
Project description:Fluoroquinolone antibiotics, a common antibiotic for the treatment of Pseudomonas aeruginosa infection, are facing challenges due to the rapid evolution of bacterial resistance. Through designed evolutionary experiments in vitro, we find that there are significant differences in evolutionary trajectories and outcomes of resistant bacteria obtained in different induction modes, among which fitness benefit of resistant strains obtained in high-dose induction mode under high level of antibiotic is significantly higher than that of wild-type strain, and collateral sensitivity to aminoglycosides and some other antibiotics will be obtained. Resistance strains obtained in the low-dose induction mode exhibit higher heterogeneity, which is accompanied by multiple drug resistance (MDR). Through second generation resequencing and proteomic techniques, overexpression of MexCD-OprJ efflux pump induced by mutations in the nfxB gene significantly improved the fitness benefit of Pseudomonas aeruginosa PAO1 under high level of fluoroquinolones. This is the precondition of the further evolution of the fleroxacin-resistant strains in the high dose induction mode, the addition of the efflux pump inhibitor phenylalanyl arginyl β-naphthylamide (PAβN) could effectively repress the evolution of bacterial resistance in the high dose induction mode. Fleroxacin use followed by gentamicin helped drive infectious P.aeruginosa to extinction, causing nfxB mutation to cause collateral sensitivity to gentamicin.
2025-02-15 | PXD044054 | Pride
Project description:An antivirulence approach targets bacterial virulence rather than cell viability in the antibiotic approach that can readily lead to drug resistance. Opportunistic human pathogen Pseudomonas aeruginosa produces a variety of virulence factors, and biofilm cells of this bacterium are much more resistant to antibiotics than planktonic cells. To identify novel inorganic antivirulence compounds, the dual screenings of thirty-six metal ions were performed to identify that zinc ions and ZnO nanoparticle inhibited the pyocyanin production and biofilm formation in P. aeruginosa without affecting the growth of planktonic cells. Moreover, zinc ion and ZnO nanoparticle markedly reduced the production of 2-heptyl-3-hydroxy-4(1H)-quinolone and siderophore pyochelin, while increased the production of another sideropore pyoverdine and swarming motility. Further, zinc ion and ZnO nanoparticle clearly suppressed hemolytic activity in P. aeruginosa. Transcriptome analyses showed that ZnO nanoparticle induced zinc cation efflux pump czc operon, porin genes (oprD and opdT), and Pseudomonas type III repressor A ptrA, while repressed pyocyanin-related phz operon, which partially explains the phenotypic changes. Overall, ZnO nanoparticle is a potential candidate for use in an antivirulence approach against persistent P. aeruginosa infection. P. aeruginosa Genechip Genome Array (Affymetrix, P/N 900339) was used in order to study the cells after the addition of ZnO nanoparticles. DNA microarray analysis with one biological replicate was performed with an Affymetrix system. P. aeruginosa was inoculated in 25 ml of LB medium in 250 ml shaker flasks with overnight cultures (1 : 100 dilution). Cells were cultured for 5 h with shaking at 250 rpm with and without ZnO nanoparticles (1 mM). Before sample collection, RNase inhibitor (RNAlater, Ambion, TX, USA) was added, and the cells were immediately chilled with dry ice and 95% ethanol (to prevent RNA degradation) for 30 s before centrifugation at 16,000 g for 2 min. The cell pellets were immediately frozen with dry ice and stored at –80°C. Total RNA was isolated using a Qiagen RNeasy mini Kit (Valencia, CA, USA).
2015-05-25 | E-GEOD-46947 | biostudies-arrayexpress
Project description:Pseudomonas aeruginosa airway infection is the primary cause of death in Cystic Fibrosis (CF). During early infection P. aeruginosa produces multiple virulence factors, which cause acute pulmonary disease and are largely regulated by quorum sensing (QS) intercellular signalling networks. Longitudinal clinical studies have observed the loss, through adaptive mutation, of QS and QS-related virulence in late chronic infection. Although the mechanisms are not understood, infection with QS mutants has been linked to a worse outcome for CF patients. By comparing QS-active and QS-inactive P. aeruginosa CF isolates, we have identified novel virulence factors and pathways associated with QS disruption. In particular, we noted factors implicating increased intra-phagocyte survival. Our data present novel targets as candidates for future CF therapies. Some of these targets are already the subject of drug development programmes for the treatment of other bacterial pathogens and may provide cross-over benefit to the CF population. Refer to individual Series. This SuperSeries is composed of the following subset Series: GSE25128: Gene expression data from Pseudomonas aeruginosa strains isolated from cystic fibrosis lung infections GSE25129: Comparative genomic hybridisation data from Pseudomonas aeruginosa strains isolated from cystic fibrosis lung infections
2010-11-04 | E-GEOD-25130 | biostudies-arrayexpress
Project description:The gene encoding elongation factor G, fusA1, is frequently mutated in clinical isolates of Pseudomonas aeruginosa from patients with cystic fibrosis. Recent work has shown that fusA1 mutants often display elevated aminoglycoside resistance due to increased expression of the aminoglycoside efflux pump, MexXY. We isolated a spontaneous gentamicin-resistant fusA1 mutant (FusA1-P443L) in which mexXY expression was increased. We compared the transcriptome of this fusA1 mutant (EMC1) with the P. aeruginosa PAO1-derived progenitor strain (EMC0) and complemented mutant strain expressing the wild-type fusA1 gene in trans (EMC1*).
2020-09-16 | E-MTAB-8690 | biostudies-arrayexpress