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Cell Metabolism Oct 2023Pseudomonas aeruginosa is a common cause of pulmonary infection. As a Gram-negative pathogen, it can initiate a brisk and highly destructive inflammatory response;...
Pseudomonas aeruginosa is a common cause of pulmonary infection. As a Gram-negative pathogen, it can initiate a brisk and highly destructive inflammatory response; however, most hosts become tolerant to the bacterial burden, developing chronic infection. Using a murine model of pneumonia, we demonstrate that this shift from inflammation to disease tolerance is promoted by ketogenesis. In response to pulmonary infection, ketone bodies are generated in the liver and circulate to the lungs where they impose selection for P. aeruginosa strains unable to display surface lipopolysaccharide (LPS). Such keto-adapted LPS strains fail to activate glycolysis and tissue-damaging cytokines and, instead, facilitate mitochondrial catabolism of fats and oxidative phosphorylation (OXPHOS), which maintains airway homeostasis. Within the lung, P. aeruginosa exploits the host immunometabolite itaconate to further stimulate ketogenesis. This environment enables host-P. aeruginosa coexistence, supporting both pathoadaptive changes in the bacteria and the maintenance of respiratory integrity via OXPHOS.
Topics: Mice; Animals; Pseudomonas aeruginosa; Lipopolysaccharides; Lung; Inflammation; Ketone Bodies
PubMed: 37793346
DOI: 10.1016/j.cmet.2023.09.001 -
Biometals : An International Journal on... Aug 2023In the genus Pseudomonas, zinc homeostasis is mediated by a complete set of import and export systems, whose expression is precisely controlled by three transcriptional... (Review)
Review
In the genus Pseudomonas, zinc homeostasis is mediated by a complete set of import and export systems, whose expression is precisely controlled by three transcriptional regulators: Zur, CzcR and CadR. In this review, we describe in detail our current knowledge of these systems, their regulation, and the biological significance of zinc homeostasis, taking Pseudomonas aeruginosa as our paradigm. Moreover, significant parts of this overview are dedicated to highlight interactions and cross-regulations between zinc and copper import/export systems, and to shed light, through a review of the literature and comparative genomics, on differences in gene complement and function across the whole Pseudomonas genus. The impact and importance of zinc homeostasis in Pseudomonas and beyond will be discussed throughout this review.
Topics: Pseudomonas; Zinc; Homeostasis; Pseudomonas aeruginosa; Copper; Bacterial Proteins; Gene Expression Regulation, Bacterial
PubMed: 36472780
DOI: 10.1007/s10534-022-00475-5 -
International Journal of Molecular... Jul 2023is a pathogen capable of colonizing virtually every human tissue. The host colonization competence and versatility of this pathogen are powered by a wide array of... (Review)
Review
is a pathogen capable of colonizing virtually every human tissue. The host colonization competence and versatility of this pathogen are powered by a wide array of virulence factors necessary in different steps of the infection process. This includes factors involved in bacterial motility and attachment, biofilm formation, the production and secretion of extracellular invasive enzymes and exotoxins, the production of toxic secondary metabolites, and the acquisition of iron. Expression of these virulence factors during infection is tightly regulated, which allows their production only when they are needed. This process optimizes host colonization and virulence. In this work, we review the intricate network of transcriptional regulators that control the expression of virulence factors in , including one- and two-component systems and σ factors. Because inhibition of virulence holds promise as a target for new antimicrobials, blocking the regulators that trigger the production of virulence determinants in is a promising strategy to fight this clinically relevant pathogen.
Topics: Humans; Virulence; Pseudomonas aeruginosa; Virulence Factors; Exotoxins; Quorum Sensing; Biofilms; Bacterial Proteins; Pseudomonas Infections
PubMed: 37569271
DOI: 10.3390/ijms241511895 -
Infection and Immunity Aug 2023The ubiquitous bacterial pathogen Pseudomonas aeruginosa is responsible for severe infections in patients with burns, cystic fibrosis, and neutropenia. Biofilm formation...
The ubiquitous bacterial pathogen Pseudomonas aeruginosa is responsible for severe infections in patients with burns, cystic fibrosis, and neutropenia. Biofilm formation gives physical refuge and a protected microenvironment for sessile cells, rendering cure by antibiotics a challenge. Bacteriophages have evolved to prey on these biofilms over millions of years, using hydrolases and depolymerases to penetrate biofilms and reach cellular targets. Here, we assessed how a newly discovered KMV-like phage (ΦJB10) interacts with antibiotics to treat P. aeruginosa more effectively in both planktonic and biofilm forms. By testing representatives of four classes of antibiotics (cephalosporins, aminoglycosides, fluoroquinolones, and carbapenems), we demonstrated class-dependent interactions between ΦJB10 and antibiotics in both biofilm clearance and P. aeruginosa killing. Despite identifying antagonism between some antibiotic classes and ΦJB10 at early time points, all classes showed neutral to favorable interactions with the phage at later time points. In one notable example where the antibiotic alone had poor activity against both biofilm and high-density planktonic cells, we found that addition of ΦJB10 demonstrated synergy and resulted in effective treatment of both. Further, ΦJB10 seemed to act as an adjuvant to several antibiotics, reducing the concentration of antibiotics required to ablate the biofilm. This report shows that phages such as ΦJB10 may be valuable additions to the armamentarium against difficult-to-treat biofilm-based infections.
Topics: Humans; Anti-Bacterial Agents; Pseudomonas Phages; Pseudomonas Infections; Bacteriophages; Cephalosporins; Biofilms; Pseudomonas aeruginosa
PubMed: 37404162
DOI: 10.1128/iai.00065-23 -
Journal of Bacteriology May 2024is a significant cause of global morbidity and mortality. Although it is often regarded as an extracellular pathogen toward human cells, numerous investigations report... (Review)
Review
is a significant cause of global morbidity and mortality. Although it is often regarded as an extracellular pathogen toward human cells, numerous investigations report its ability to survive and replicate within host cells, and additional studies demonstrate specific mechanisms enabling it to adopt an intracellular lifestyle. This ability of remains less well-investigated than that of other intracellular bacteria, although it is currently gaining attention. If intracellular bacteria are not killed after entering host cells, they may instead receive protection from immune recognition and experience reduced exposure to antibiotic therapy, among additional potential advantages shared with other facultative intracellular pathogens. For this review, we compiled studies that observe intracellular across strains, cell types, and experimental systems , as well as contextualize these findings with the few studies that report similar observations . We also seek to address key findings that drove the perception that remains extracellular in order to reconcile what is currently understood about intracellular pathogenesis and highlight open questions regarding its contribution to disease.
Topics: Pseudomonas aeruginosa; Humans; Pseudomonas Infections; Animals; Host-Pathogen Interactions
PubMed: 38597609
DOI: 10.1128/jb.00109-24 -
Ugeskrift For Laeger Jan 2024We present a case report detailing therapeutic application of two lytic antipseudomonal bacteriophages to treat a chronic relapsing Pseudomonas aeruginosa infection of a...
We present a case report detailing therapeutic application of two lytic antipseudomonal bacteriophages to treat a chronic relapsing Pseudomonas aeruginosa infection of a prosthetic aortic graft. As there are currently no Danish laboratories offering phages for clinical therapy, and this case, to our knowledge represents the first applied phage therapy in Denmark, the practical and regulatory aspects of offering this treatment option in Denmark is briefly reviewed along with the clinical case.
Topics: Humans; Bacteriophages; Pseudomonas; Pseudomonas Phages; Blood Vessel Prosthesis; Pseudomonas aeruginosa
PubMed: 38305316
DOI: 10.61409/V09230617 -
MBio Aug 2023Transporters of the resistance-nodulation-cell division (RND) superfamily of proteins are the dominant multidrug efflux power of Gram-negative bacteria. The major RND...
Transporters of the resistance-nodulation-cell division (RND) superfamily of proteins are the dominant multidrug efflux power of Gram-negative bacteria. The major RND efflux pump of is MexAB-OprM, in which the inner membrane transporter MexB is responsible for the recognition and binding of compounds. The high importance of this pump in clinical antibiotic resistance made it a subject of intense investigations and a promising target for the discovery of efflux pump inhibitors. This study is focused on a series of peptidomimetic compounds developed as effective inhibitors of MexAB-OprM. We performed multi-copy molecular dynamics simulations, machine-learning (ML) analyses, and site-directed mutagenesis of MexB to investigate interactions of MexB with representatives of efflux avoiders, substrates, and inhibitors. The analysis of both direct and water-mediated protein-ligand interactions revealed characteristic patterns for each class, highlighting significant differences between them. We found that efflux avoiders poorly interact with the access binding site of MexB, and inhibition engages amino acid residues that are not directly involved in binding and transport of substrates. In agreement, machine-learning models selected different residues predictive of MexB substrates and inhibitors. The differences in interactions were further validated by site-directed mutagenesis. We conclude that the substrate translocation and inhibition pathways of MexB split at the interface (between the main putative binding sites) and at the deep binding pocket and that interactions outside of the hydrophobic patch contribute to the inhibition of MexB. This molecular-level information could help in the rational design of new inhibitors and antibiotics less susceptible to the efflux mechanism. IMPORTANCE Multidrug transporters recognize and expel from cells a broad range of ligands including their own inhibitors. The difference between the substrate translocation and inhibition routes remains unclear. In this study, machine learning and computational and experimental approaches were used to understand dynamics of MexB interactions with its ligands. Our results show that some ligands engage a certain combination of polar and charged residues in MexB binding sites to be effectively expelled into the exit funnel, whereas others engage aromatic and hydrophobic residues that slow down or hinder the next step in the transporter cycle. These findings suggest that all MexB ligands fit into this substrate-inhibitor spectrum depending on their physico-chemical structures and properties.
Topics: Pseudomonas aeruginosa; Bacterial Outer Membrane Proteins; Ligands; Microbial Sensitivity Tests; Membrane Transport Proteins
PubMed: 37493633
DOI: 10.1128/mbio.01403-23 -
Current Opinion in Chemical Biology Feb 2024Exopolysaccharides are produced and excreted by bacteria in the generation of biofilms to provide a protective environment. These polysaccharides are generally generated... (Review)
Review
Exopolysaccharides are produced and excreted by bacteria in the generation of biofilms to provide a protective environment. These polysaccharides are generally generated as heterogeneous polymers of varying length, featuring diverse substitution patterns. To obtain well-defined fragments of these polysaccharides, organic synthesis often is the method of choice, as it allows for full control over chain length and the installation of a pre-determined substitution pattern. This review presents several recent syntheses of exopolysaccharide fragments of Pseudomonas aeruginosa and Staphylococcus aureus and illustrates how these have been used to study biosynthesis enzymes and generate synthetic glycoconjugate vaccines.
Topics: Polysaccharides, Bacterial; Biofilms; Pseudomonas aeruginosa
PubMed: 38134611
DOI: 10.1016/j.cbpa.2023.102418 -
Frontiers in Immunology 2023Serious infections of (PA) in hospitals and the emergence and increase of multidrug resistance have raised an urgent need for effective vaccines. However, no vaccine...
INTRODUCTION
Serious infections of (PA) in hospitals and the emergence and increase of multidrug resistance have raised an urgent need for effective vaccines. However, no vaccine has been approved to date. One possible reason for this is the limited immune response due to the lack of an efficient delivery system. Self-assembled ferritin nanoparticles are good carriers of heterogeneous antigens, which enhance the activation of immunological responses.
METHODS
In this study, two well-studied antigen candidates, PcrV and OprI, were selected and connected to the ferritin nanoparticle by the Spytag/SpyCatcher system to generate the nanovaccine rePO-FN.
RESULTS
Compared to recombinant PcrV-OprI formulated with aluminum adjuvants, intramuscular immunization with adjuvant-free rePO-FN induced quick and efficient immunity and conferred protection against PA pneumonia in mice. In addition, intranasal immunization with adjuvant-free rePO-FN enhanced protective mucosal immunity. Moreover, rePO-FN exhibited good biocompatibility and safety.
DISCUSSION
Our results suggest that rePO-FN is a promising vaccine candidate, as well as, provide additional evidence for the success of ferritin-based nanovaccines.
Topics: Animals; Mice; Antigens, Bacterial; Bacterial Toxins; Pseudomonas aeruginosa; Vaccines; Adjuvants, Immunologic; Adjuvants, Pharmaceutic
PubMed: 37415986
DOI: 10.3389/fimmu.2023.1184863 -
PLoS Pathogens Aug 2023Pseudomonas aeruginosa (P.a.) infection accounts for nearly 20% of all cases of hospital acquired pneumonia with mortality rates >30%. P.a. infection induces a robust...
Pseudomonas aeruginosa (P.a.) infection accounts for nearly 20% of all cases of hospital acquired pneumonia with mortality rates >30%. P.a. infection induces a robust inflammatory response, which ideally enhances bacterial clearance. Unfortunately, excessive inflammation can also have negative effects, and often leads to cardiac dysfunction with associated morbidity and mortality. However, it remains unclear how P.a. lung infection causes cardiac dysfunction. Using a murine pneumonia model, we found that P.a. infection of the lungs led to severe cardiac left ventricular dysfunction and electrical abnormalities. More specifically, we found that neutrophil recruitment and release of S100A8/A9 in the lungs activates the TLR4/RAGE signaling pathways, which in turn enhance systemic inflammation and subsequent cardiac dysfunction. Paradoxically, global deletion of S100A8/A9 did not improve but aggravated cardiac dysfunction and mortality likely due to uncontrolled bacterial burden in the lungs and heart. Our results indicate that P.a. infection induced release of S100A8/9 is double-edged, providing increased risk for cardiac dysfunction yet limiting P.a. growth.
Topics: Animals; Mice; Pseudomonas aeruginosa; Heart; Inflammation; Pseudomonas Infections; Lung; Heart Diseases
PubMed: 37624851
DOI: 10.1371/journal.ppat.1011573