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PLoS Pathogens Aug 2023Pseudomonas aeruginosa (P. aeruginosa) can cause severe acute infections, including pneumonia and sepsis, and cause chronic infections, commonly in patients with...
Pseudomonas aeruginosa (P. aeruginosa) can cause severe acute infections, including pneumonia and sepsis, and cause chronic infections, commonly in patients with structural respiratory diseases. However, the molecular and pathophysiological mechanisms of P. aeruginosa respiratory infection are largely unknown. Here, we performed assays for transposase-accessible chromatin using sequencing (ATAC-seq), transcriptomics, and quantitative mass spectrometry-based proteomics and ubiquitin-proteomics in P. aeruginosa-infected lung tissues for multi-omics analysis, while ATAC-seq and transcriptomics were also examined in P. aeruginosa-infected mouse macrophages. To identify the pivotal factors that are involved in host immune defense, we integrated chromatin accessibility and gene expression to investigate molecular changes in P. aeruginosa-infected lung tissues combined with proteomics and ubiquitin-proteomics. Our multi-omics investigation discovered a significant concordance for innate immunological and inflammatory responses following P. aeruginosa infection between hosts and alveolar macrophages. Furthermore, we discovered that multi-omics changes in pioneer factors Stat1 and Stat3 play a crucial role in the immunological regulation of P. aeruginosa infection and that their downstream molecules (e.g., Fas) may be implicated in both immunosuppressive and inflammation-promoting processes. Taken together, these findings indicate that transcription factors and their downstream signaling molecules play a critical role in the mobilization and rebalancing of the host immune response against P. aeruginosa infection and may serve as potential targets for bacterial infections and inflammatory diseases, providing insights and resources for omics analyses.
Topics: Animals; Mice; Pseudomonas aeruginosa; Multiomics; Pneumonia; Chromatin; Ubiquitins
PubMed: 37643174
DOI: 10.1371/journal.ppat.1011570 -
Virus Research Oct 2023Pseudomonas aeruginosa is a clinically common conditionally pathogenic bacterium, and the abuse of antibiotics has exacerbated its drug resistance in recent years. This...
Pseudomonas aeruginosa is a clinically common conditionally pathogenic bacterium, and the abuse of antibiotics has exacerbated its drug resistance in recent years. This has resulted in extensive reports about the usage of Pseudomonas aeruginosa phage as a novel antibacterial drug. In this study, we isolated a novel phage HZ2201 with a broad lytic spectrum. The lytic rate of this phage against Pseudomonas aeruginosa reached 78.38% (29/37), including 25 multi-drug- and carbapenem-resistant Pseudomonas aeruginosa strains. Transmission electron microscopy revealed that phage HZ2201 belongs to the class Caudoviricetes. Biological characterization showed that phage HZ2201 had an latent period of 40 min, a lytic period of 20 min, and a burst size of 440 PFU/cell, with improved tolerance to temperature and pH. Considering genomic analysis, the HZ2201 genome was a circular double-stranded DNA with a size of 45,431 bp and a guanine-cytosine (G + C) content of 52.16%, and contained 3 tRNAs. 27 of the 74 open reading frames (ORFs) annotated by the Rapid Annotation using Subsystem Technology (RAST) tool could be matched to the genomes of known functions, and no genes related to virulence and antibiotic resistance were found. The phylogenetic tree suggests that phage HZ2201 is highly related to the phage ZCPS1 and PaP3, and ORF57 and ORF17 are predicted to encode a holin and an endolysin, respectively. Cell lysis by HZ2201 proceeds through the holin-endolysin system, suggesting that it is a novel phage. Additionally, we demonstrated that phage HZ2201 has a high inhibitory capacity against Pseudomonas aeruginosa biofilms. The results of our study suggest that phage HZ2201 is a novel potential antimicrobial agent for treating drug-resistant Pseudomonas aeruginosa infection.
Topics: Bacteriophages; Pseudomonas aeruginosa; Phylogeny; Pseudomonas Phages; Genomics; Genome, Viral; Biofilms
PubMed: 37532140
DOI: 10.1016/j.virusres.2023.199184 -
Phytomedicine : International Journal... Oct 2023After almost 100 years since evidence of biofilm mode of growth and decades of intensive investigation about their formation, regulatory pathways and mechanisms of... (Review)
Review
BACKGROUND
After almost 100 years since evidence of biofilm mode of growth and decades of intensive investigation about their formation, regulatory pathways and mechanisms of antimicrobial tolerance, nowadays there are still no therapeutic solutions to eradicate bacterial biofilms and their biomedical related issues.
PURPOSE
This review intends to provide a comprehensive summary of the recent and most relevant published studies on plant-based products, or their isolated compounds with antibiofilm activity mechanisms of action or identified molecular targets against bacterial biofilms. The objective is to offer a new perspective of most recent data for clinical researchers aiming to prevent or eliminate biofilm-associated infections caused by bacterial pathogens.
METHODS
The search was performed considering original research articles published on PubMed, Web of Science and Scopus from 2015 to April 2023, using keywords such as "antibiofilm", "antivirulence", "phytochemicals" and "plant extracts".
RESULTS
Over 180 articles were considered for this review with a focus on the priority human pathogens listed by World Health Organization, including Pseudomonas aeruginosa, Staphylococcus aureus, Klebsiella pneumoniae and Escherichia coli. Inhibition and detachment or dismantling of biofilms formed by these pathogens were found using plant-based extract/products or derivative compounds. Although combination of plant-based products and antibiotics were recorded and discussed, this topic is currently poorly explored and only for a reduced number of bacterial species.
CONCLUSIONS
This review clearly demonstrates that plant-based products or derivative compounds may be a promising therapeutic strategy to eliminate bacterial biofilms and their associated infections. After thoroughly reviewing the vast amount of research carried out over years, it was concluded that plant-based products are mostly able to prevent biofilm formation through inhibition of quorum sensing signals, but also to disrupt mature biofilms developed by multidrug resistant bacteria targeting the biofilm extracellular polymeric substance. Flavonoids and phenolic compounds seemed the most effective against bacterial biofilms.
Topics: Humans; Extracellular Polymeric Substance Matrix; Biofilms; Anti-Bacterial Agents; Anti-Infective Agents; Bacteria; Pseudomonas aeruginosa; Microbial Sensitivity Tests
PubMed: 37499434
DOI: 10.1016/j.phymed.2023.154973 -
Microbial Cell Factories Aug 2023Pyocyanin is a secondary metabolite secreted by P. aeruginosa. It is a redox-active blue/green phenazine pigment that has various beneficial applications. The present...
BACKGROUND
Pyocyanin is a secondary metabolite secreted by P. aeruginosa. It is a redox-active blue/green phenazine pigment that has various beneficial applications. The present study aims at screening the production of pyocyanin among clinical and environmental P. aeruginosa isolates in Dakahlya governorate, Egypt. Thereafter, large-scale production, purification, structure elucidation, and assessment of the biological activity of the highest pyocyanin producers were targeted.
RESULTS
Pyocyanin from the highest clinical (PsC05) and environmental (PsE02) producers were subjected to large-scale production, followed by purification using silica gel column. Pyocyanin was characterized using TLC, UV-Vis, H NMR, and FTIR spectroscopy to confirm its structure and purity. Purified pyocyanin showed remarkable antimicrobial efficacy against all tested food-borne pathogens, MDR/XDR clinically isolated bacteria and C. albicans. Furthermore, it showed a substantial effect on biofilm inhibition and eradication of pre-formed biofilm against strong biofilm producing bacterial pathogens. However, it had limited antibiofilm activity against C. albicans. Pyocyanin from PsC05 had higher antioxidant and radicals scavenging activity than that from PsE02 as determined by FRAP, DPPH, and ABTS assays. Likewise, pyocyanin from PsC05 was more active against tested cancer cell lines, especially human Breast Cancer (MCF-7) and Colorectal Carcinoma (HCT-116), than that from PsE02. More importantly, it showed minimal cytotoxicity to normal cells.
CONCLUSIONS
P. aeruginosa clinical and environmental isolates produce pyocyanin pigment in varying amounts. Pyocyanin exhibits substantial anti-bacterial, and anti-fungal activity; thus, enhancing its medical applicability. It could be used to inhibit and/or eradicate biofilm from the surfaces of medical devices which is a chief source of nosocomial infections. Its antioxidant along with cytotoxic activity against cancer cell lines, make it a promising contender for use as a substitute for synthetic agents in cancer treatment.
Topics: Humans; Pyocyanine; Antioxidants; Pseudomonas aeruginosa; Biofilms; Biological Assay; Candida albicans
PubMed: 37644606
DOI: 10.1186/s12934-023-02169-0 -
Cell Reports. Medicine Oct 2023Nearly one-half of patients with cystic fibrosis (CF) carry the homozygous F508del mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene but...
Nearly one-half of patients with cystic fibrosis (CF) carry the homozygous F508del mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene but exhibit variable lung function phenotypes. How adaptive immunity influences their lung function remains unclear, particularly the serological antibody responses to antigens from mucoid Pseudomonas in sera from patients with CF with varying lung function. Sera from patients with CF with reduced lung function show higher anti-outer membrane protein I (OprI) immunoglobulin G1 (IgG1) titers and greater antibody-mediated complement deposition. Induction of anti-OprI antibody isotypes with complement activity enhances lung inflammation in preclinical mouse models. This enhanced inflammation is absent in immunized Rag2 mice and is transferrable to unimmunized mice through sera. In a CF cohort undergoing treatment with elexacaftor-tezacaftor-ivacaftor, the declination in anti-OprI IgG1 titers is associated with lung function improvement and reduced hospitalizations. These findings suggest that antibody responses to specific Pseudomonas aeruginosa (PA) antigens worsen lung function in patients with CF.
Topics: Humans; Animals; Mice; Cystic Fibrosis; Pseudomonas; Pseudomonas aeruginosa; Lung; Immunoglobulin G
PubMed: 37852181
DOI: 10.1016/j.xcrm.2023.101210 -
Nature Communications Jun 2023Bacteriophage therapy has been suggested as an alternative or complementary strategy for the treatment of multidrug resistant (MDR) bacterial infections. Here, we report...
Bacteriophage therapy has been suggested as an alternative or complementary strategy for the treatment of multidrug resistant (MDR) bacterial infections. Here, we report the favourable clinical evolution of a 41-year-old male patient with a Kartagener syndrome complicated by a life-threatening chronic MDR Pseudomonas aeruginosa infection, who is treated successfully with iterative aerosolized phage treatments specifically directed against the patient's isolate. We follow the longitudinal evolution of both phage and bacterial loads during and after phage administration in respiratory samples. Phage titres in consecutive sputum samples indicate in patient phage replication. Phenotypic analysis and whole genome sequencing of sequential bacterial isolates reveals a clonal, but phenotypically diverse population of hypermutator strains. The MDR phenotype in the collected isolates is multifactorial and mainly due to spontaneous chromosomal mutations. All isolates recovered after phage treatment remain phage susceptible. These results demonstrate that clinically significant improvement is achievable by personalised phage therapy even in the absence of complete eradication of P. aeruginosa lung colonization.
Topics: Male; Humans; Bacteriophages; Pseudomonas aeruginosa; Lung; Drug Resistance, Multiple, Bacterial; Pneumonia; Persistent Infection; Pseudomonas Infections; Anti-Bacterial Agents
PubMed: 37369702
DOI: 10.1038/s41467-023-39370-z -
Proceedings of the National Academy of... Jul 2023The outer membrane of Gram-negative bacteria is unique in both structure and function. The surface-exposed outer leaflet is composed of lipopolysaccharide, while the...
The outer membrane of Gram-negative bacteria is unique in both structure and function. The surface-exposed outer leaflet is composed of lipopolysaccharide, while the inner leaflet is composed of glycerophospholipids. This lipid asymmetry creates mechanical strength, lowers membrane permeability, and is necessary for virulence in many pathogens. Glycerophospholipids that mislocalize to the outer leaflet are removed by the Mla pathway, which consists of the outer membrane channel MlaA, the periplasmic lipid carrier MlaC, and the inner membrane transporter MlaBDEF. The opportunistic pathogen has two proteins of the MlaA family: PA2800 and PA3239. Here, we show that PA2800 is part of a canonical Mla pathway, while PA3239 functions with the putative lipase PA3238. While loss of either pathway individually has little to no effect on outer membrane integrity, loss of both pathways weakens the outer membrane permeability barrier and increases production of the secondary metabolite pyocyanin. We propose that mislocalized glycerophospholipids are removed from the outer leaflet by PA3239 (renamed MlaZ), transferred to PA3238 (renamed MlaY), and degraded. This pathway streamlines recycling of glycerophospholipid degradation products by removing glycerophospholipids from the outer leaflet prior to degradation.
Topics: Membrane Lipids; Pseudomonas aeruginosa; Biological Transport; Phospholipases; Bacterial Outer Membrane Proteins; Cell Membrane; Glycerophospholipids
PubMed: 37463202
DOI: 10.1073/pnas.2302546120 -
Journal of Bacteriology Aug 2023Pseudomonas aeruginosa is an opportunistic pathogen heavily implicated in chronic diseases. Immunocompromised patients that become infected with P. aeruginosa usually... (Review)
Review
Pseudomonas aeruginosa is an opportunistic pathogen heavily implicated in chronic diseases. Immunocompromised patients that become infected with P. aeruginosa usually are afflicted with a lifelong chronic infection, leading to worsened patient outcomes. The complement system is an integral piece of the first line of defense against invading microorganisms. Gram-negative bacteria are thought to be generally susceptible to attack from complement; however, P. aeruginosa can be an exception, with certain strains being serum resistant. Various molecular mechanisms have been described that confer P. aeruginosa unique resistance to numerous aspects of the complement response. In this review, we summarize the current published literature regarding the interactions of P. aeruginosa and complement, as well as the mechanisms used by P. aeruginosa to exploit various complement deficiencies and the strategies used to disrupt or hijack normal complement activities.
Topics: Humans; Pseudomonas aeruginosa; Pseudomonas Infections; Complement System Proteins
PubMed: 37436150
DOI: 10.1128/jb.00018-23 -
Applied Microbiology and Biotechnology Aug 2023The biocatalysis of β-myrcene into value-added compounds, with enhanced organoleptic/therapeutic properties, may be performed by resorting to specialized enzymatic...
The biocatalysis of β-myrcene into value-added compounds, with enhanced organoleptic/therapeutic properties, may be performed by resorting to specialized enzymatic machinery of β-myrcene-biotransforming bacteria. Few β-myrcene-biotransforming bacteria have been studied, limiting the diversity of genetic modules/catabolic pathways available for biotechnological research. In our model Pseudomonas sp. strain M1, the β-myrcene catabolic core-code was identified in a 28-kb genomic island (GI). The lack of close homologs of this β-myrcene-associated genetic code prompted a bioprospection of cork oak and eucalyptus rhizospheres, from 4 geographic locations in Portugal, to evaluate the environmental diversity and dissemination of the β-myrcene-biotransforming genetic trait (Myr). Soil microbiomes were enriched in β-myrcene-supplemented cultures, from which β-myrcene-biotransforming bacteria were isolated, belonging to Alphaproteobacteria, Betaproteobacteria, Gammaproteobacteria, and Sphingobacteriia classes. From a panel of representative Myr isolates that included 7 bacterial genera, the production of β-myrcene derivatives previously reported in strain M1 was detected in Pseudomonas spp., Cupriavidus sp., Sphingobacterium sp., and Variovorax sp. A comparative genomics analysis against the genome of strain M1 found the M1-GI code in 11 new Pseudomonas genomes. Full nucleotide conservation of the β-myrcene core-code was observed throughout a 76-kb locus in strain M1 and all 11 Pseudomonas spp., resembling the structure of an integrative and conjugative element (ICE), despite being isolated from different niches. Furthermore, the characterization of isolates not harboring the Myr-related 76-kb locus suggested that they may biotransform β-myrcene via alternative catabolic loci, being thereby a novel source of enzymes and biomolecule catalogue for biotechnological exploitation. KEY POINTS: • The isolation of 150 Myr bacteria hints the ubiquity of such trait in the rhizosphere. • The Myr trait is spread across different bacterial taxonomic classes. • The core-code for the Myr trait was detected in a novel ICE, only found in Pseudomonas spp.
Topics: Rhizosphere; Acyclic Monoterpenes; Bacteria; Pseudomonas
PubMed: 37405434
DOI: 10.1007/s00253-023-12650-w -
Annals of the American Thoracic Society Feb 2024
Topics: Humans; Retrospective Studies; COVID-19; Bronchiectasis; Pseudomonas aeruginosa; Insurance
PubMed: 38299923
DOI: 10.1513/AnnalsATS.202312-1018ED