Collateral sensitivity of CF isolates
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PROVIDER: PRJEB12206 | ENA |
REPOSITORIES: ENA
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Project description:To provide a more detailed survey of adaptive changes in the physiology of P. aeruginosa (PA) during long-term infection of the cystic fibrosis (CF) lung, we performed a comparative proteome and transcriptome analysis of a set of isogenic sequential non-mutator and mutator isolates from three selected CF patients. Recently, we showed that during CF lung persistence PA mutators converge to a virulence-attenuated phenotype. In this study, we demonstrate that besides virulence-associated traits (VATs) the adaptation process of PA predominantly comprises metabolic pathways. In end-stage mutator strains, transcripts of genes encoding VATs, chemotaxis, degradation of aromatic compounds and several two-component regulatory systems were decreased. In contrast, several transcripts of genes or proteins involved in metabolism of fatty acids, nucleotides, amino acids and the generation of energy were increased. Of particular interest is the increased expression level of genes involved in (i) the anaerobic arginine-deiminase pathway, (ii) the anaerobic respiration such as nitrate-uptake protein OprF, redox-active azurin and cytchrome c551 peroxidase, (iii) the micro-aerobic respiration such as high oxygen-affinity cytochrome oxidase cbb3 (iv) the tricarboxylic acid cycle (TCA), glyoxylate shunt and anaplerotic carboxylation reactions to oxaloacetate. Strikingly, an increased transcription of the anaerobic regulator gene anr correlates with the up-regulation of ANR-dependent genes. In conclusion, these changes in transcriptome and proteome indicate an adaptive shift towards constitutive expression of genes of metabolic pathways obviously required for growth under micro-aerobic and nutritional conditions of suppurative CF lung tissue. Finally, these results provide us with new targets for antimicrobial agents and biomarkers reflecting adaptation of PA towards progressive CF lung disease. Experiment Overall Design: P. aeruginosa isolates recovered from different time points of chronic cystic fibrosis lung disease were cultered in vitro, harvested for RNA extraction and hybridization on Affymetrix microarrays. We compared the transcriptome (triplicate microarrays) of early non-mutator P. aeruginosa isolates with late mutator isolates with high mutation frequency probably the driving force of an efficient adaptation to changing environements to conclude from differences in gene expression to the requirements of CF lung environment. Experiment Overall Design: Second publication of array data to be added later
2009-06-08 | E-GEOD-10362 | biostudies-arrayexpress
Project description:Cationic antimicrobial peptides (CAPs) are promising novel alternatives to conventional antibacterial agents, but the overlap in resistance mechanisms between small-molecule antibiotics and CAPs is unknown. Does evolution of antibiotic resistance decrease (cross-resistance) or increase (collateral sensitivity) susceptibility to CAPs? We systematically addressed this issue by studying the susceptibilities of a comprehensive set of antibiotic resistant Escherichia coli strains towards 24 antimicrobial peptides. Strikingly, antibiotic resistant bacteria frequently showed collateral sensitivity to CAPs, while cross-resistance was relatively rare. We identified clinically relevant multidrug resistance mutations that simultaneously elevate susceptibility to certain CAPs. Transcriptome and chemogenomic analysis revealed that such mutations frequently alter the lipopolysaccharide composition of the outer cell membrane and thereby increase the killing efficiency of membrane-interacting antimicrobial peptides. Furthermore, we identified CAP-antibiotic combinations that rescue the activity of existing antibiotics and slow down the evolution of resistance to antibiotics. Our work provides a proof of principle for the development of peptide based antibiotic adjuvants that enhance antibiotic action and block evolution of resistance.
2018-03-29 | GSE96706 | GEO
Project description:Chronic Pseudomas aeruginosa infection in the lung is a common in people with cystic fibrosis (CF). Current therapies for CF fail to eliminate persistent bacterial infections, chronic inflammation, or irreversible lung damage. Our group engineered mesenchymal stromal cell (MSC)-derived extracellular vesicles (EVs) to carry the microRNA let-7b-5p as a dual anti-infective and anti-inflammatory treatment. In a preclinical CF mice model, we found that let-7b-5p-loaded MSC EVs reduced P. aeruginosa burden, immune cells and proinflammatory cytokines in the lungs. This research hypothesized two mechanisms of the observed effects in the mouse model: anti-inflammatory properties of the let-7b-5p-loaded MSC EVs and inhibition of antibiotic-resistant P. aeruginosa biofilm formation in CF airways. Primary human broncial epithelial cells (pHBECs) were exposed to P. aeruginosa and treated with differet MSC EV conditions. The results demonstrated that MSC EVs engineered to contain let-7b-5p effectively blocked the formation of P. aeruginosa biofilms on pHBECs while also reducing P. aeruginosa-induced inflammation by CF-pHBECs.
2025-06-16 | GSE295607 | GEO
Project description:P. aeruginosa produces serious chronic infections in hospitalized patients and immunocompromised individuals, including cystic fibrosis patients. The molecular mechanisms by which P. aeruginosa responds to antibiotics and other stresses to promote persistent infections may provide new avenues for therapeutic intervention. Azithromycin (AZM), an antibiotic frequently utilized in cystic fibrosis treatment, is thought to improve clinical outcomes through a number of mechanisms including impaired biofilm growth and quorum sensing in P. aeruginosa. However, the mechanisms underlying the transcriptional response to AZM remain unclear. Here, we interrogated the P. aeruginosa transcriptional response to AZM using a fast and affordable genome-wide approach to quantitate RNA 3-prime-ends (3pMap). We identify new riboregulators and identify a prominent role of transcription termination in the response to AZM treatment.
2021-06-08 | GSE173073 | GEO
Project description:Arrays comparing Pseudomonas aeruginosa growth in a defined synthetic cystic fibrosis sputum medium with and without aromatic amino acids. Additional arrays comparing wild-type Pseudomonas aeruginosa and phhR mutant P. aeruginosa in defined synthetic cystic fibrosis sputum medium.
2010-04-01 | E-MEXP-2593 | biostudies-arrayexpress
Project description:A shaving proteomic approach was applied to explore surface protein expression of multi- and pan-drug resistant strains of Pseudomonas aeruginosa isolated from the airways of cystic fibrosis patients with long-term chronic colonization compared to wild-type antibiotic-sensitive strains isolated from patients with recent infection.
2021-11-29 | MSV000088468 | MassIVE
Project description:Pseudomonas aeruginosa is a predominant pathogen in chronic lung infections in individuals with cystic fibrosis (CF). Epidemic strains of P. aeruginosa, such as the Liverpool Epidemic Strain (LES), are capable of transferring between CF patients and have been associated with increased hospital visits and antibiotic treatments. Comparative genomics and phenotypic assays have shown that antibiotic resistance profiles differ among LES isolates and that genotype–phenotype associations are difficult to establish for resistance phenotypes in clinical isolates of P. aeruginosa based on these comparisons alone. We compared two LES isolates, LESlike1 and LESB58, and the common laboratory strain P. aeruginosa PAO1 using label-free quantitative proteomics to more accurately predict functional differences between strains. The proteomes of the LES isolates were found to be more similar to each other than to PAO1. However, we also observed a number of differences in the abundance of proteins involved in quorum sensing, virulence, and antibiotic resistance, including in the comparison of LESlike1 and LESB58. Specifically, the proteomic data revealed a higher abundance of proteins involved in polymyxin and aminoglycoside resistance in LESlike1. Minimum inhibitory concentration assays confirmed that LESlike1 has higher resistance to antibiotics from these classes. These findings provide an example of the ability of proteomic data to complement genotypic and phenotypic studies to understand resistance in clinical isolates.
2022-05-09 | PXD025827 | Pride
Project description:Pseudomonas aeruginosa (P. aeruginosa) lung infection is a significant cause of mortality in patients with cystic fibrosis (CF). Most CF patients acquire unique P. aeruginosa strains from the environment; however clonal strains have been identified in CF communities in several countries. Two clonal strains infect 10% to 40% of patients in three CF clinics in mainland eastern Australia. The expression profiles of four planktonically-grown isolates of one Australian clonal strain (AES-2), and four non–clonal CF P. aeruginosa isolates were compared to each other and to the reference strain PAO1 using the Affymetrix P. aeruginosa PAO1 genome array, to gain insight into properties mediating the enhanced infectivity of AES-1. The isolates were subsequently grown as 3-day old biofilms and similarly extracted for RNA and compared as above. Data analysis was carried out using BIOCONDUCTOR software. Keywords: Comparative strain hybridization
2009-02-05 | GSE10304 | GEO
Project description:Pseudomonas aeruginosa (P. aeruginosa) lung infection is a significant cause of mortality in patients with cystic fibrosis (CF). Existing experimental data in our lab showed significantly different levels of virulence of "early" and "late" P. aeruginosa infection isolates in a C. elegans slow killing model. We wished to examine the expression profile of these isolates in order to explore genes that may be responsible for the observed differences. The expression profiles of two pairs of isolates (four isolates in total) were compared to each other using the Affymetrix P. aeruginosa PAO1 genome array, to gain insight into properties mediating virulence in these isolates. Data analysis was carried out using BIOCONDUCTOR software. Keywords: Comparative strain hybridization
2011-12-31 | GSE33275 | GEO
Project description:Pseudomonas aeruginosa Liverpool Epidemic Strain population study in cystic fibrosis sputum samples
| PRJEB6642 | ENA