Bacterial Persister Cells and Development of Antibiotic Resistance in Chronic Infections: An Update

British Journal of Biomedical Science, Journal Year: 2024, Volume and Issue: 81

Published: Aug. 7, 2024

The global issue of antimicrobial resistance poses significant challenges to public health. World Health Organization (WHO) has highlighted it as a major health threat, causing an estimated 700,000 deaths worldwide. Understanding the multifaceted nature antibiotic is crucial for developing effective strategies. Several physiological and biochemical mechanisms are involved in development resistance. Bacterial cells may escape bactericidal actions drugs by entering physiologically dormant state known bacterial persistence. Recent findings this field suggest that persistence can be one main sources chronic infections. tolerance developed persister could tolerate high levels antibiotics give rise offspring. These offspring attributed mechanisms, especially This review attempts shed light on persister-induced current therapeutic

Language: Английский

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Ketogenesis promotes tolerance to Pseudomonas aeruginosa pulmonary infection

Cell Metabolism, Journal Year: 2023, Volume and Issue: 35(10), P. 1767 - 1781.e6

Published: Oct. 1, 2023

Pseudomonas aeruginosa is a common cause of pulmonary infection. As Gram-negative pathogen, it can initiate brisk and highly destructive inflammatory response; however, most hosts become tolerant to the bacterial burden, developing chronic Using murine model pneumonia, we demonstrate that this shift from inflammation disease tolerance promoted by ketogenesis. In response infection, ketone bodies are generated in liver circulate lungs where they impose selection for P. strains unable display surface lipopolysaccharide (LPS). Such keto-adapted LPS fail activate glycolysis tissue-damaging cytokines and, instead, facilitate mitochondrial catabolism fats oxidative phosphorylation (OXPHOS), which maintains airway homeostasis. Within lung, exploits host immunometabolite itaconate further stimulate This environment enables host-P. coexistence, supporting both pathoadaptive changes bacteria maintenance respiratory integrity via OXPHOS.

Language: Английский

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Mechanisms of host adaptation by bacterial pathogens

FEMS Microbiology Reviews, Journal Year: 2024, Volume and Issue: 48(4)

Published: June 20, 2024

The emergence of new infectious diseases poses a major threat to humans, animals, and broader ecosystems. Defining factors that govern the ability pathogens adapt host species is therefore crucial research imperative. Pathogenic bacteria are particular concern, given dwindling treatment options amid continued expansion antimicrobial resistance. In this review, we summarize recent advancements in understanding bacterial adaptation, with an emphasis on humans related mammals. We focus particularly molecular mechanisms underlying key steps adaptation including colonization, nutrient acquisition, immune evasion, as well suggest areas for future investigation. By developing greater pathogenic bacteria, may uncover strategies target these microbes prevention environment.

Language: Английский

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Diversification of Pseudomonas aeruginosa After Inhaled Tobramycin Therapy of Cystic Fibrosis Patients: Genotypic and Phenotypic Characteristics of Paired Pre- and Post-Treatment Isolates

Microorganisms, Journal Year: 2025, Volume and Issue: 13(4), P. 730 - 730

Published: March 24, 2025

This study examines the impact of inhaled tobramycin therapy on within-host changes in P. aeruginosa strains isolated from Bulgarian patients with CF prior to and post treatment. Genotypic comparison by RAPD-PCR indicated that most pre-treatment isolates had a high similarity were genetically comparatively close other countries known increased morbidity or treatment requirements. Most post-treatment were, however, distant their counterparts, showing genotypic diversification after Phenotypic comparisons showed lower ODmax reached during groswth an lag-time isolates. All capable invasion intracellular reproduction within A549 cultured cells. The addition sub-inhibitory amounts (1/4 1/2 MIC) growth higher relative fitness (as percentage untreated control) strains. effects sub-MICs biofilm did not show such pronounced trend. However, when resazurin-based viability test was applied, advantage confirmed for both broth cultures. In spite that, according determined MIC values, all tobramycin-sensitive, data this imply development tolerance antibiotic survived

Language: Английский

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Modeling reciprocal adaptation of Staphylococcus aureus and Pseudomonas aeruginosa co-isolates in artificial sputum medium

Biofilm, Journal Year: 2025, Volume and Issue: unknown, P. 100279 - 100279

Published: April 1, 2025

Co-infections by Staphylococcus aureus and Pseudomonas aeruginosa are frequent in the airways of patients with cystic fibrosis. These co-infections show higher antibiotic tolerance vitro compared to mono-infections. In models have been developed study interspecies interactions between P. S. aureus. However, these model systems fail incorporate clinical isolates diverse phenotypes, do not reflect nutritional environment CF airway mucus, and/or biofilm mode growth observed airways. Here, we established a dual-species grown artificial sputum medium, where was inoculated before facilitate maintenance both species over time. It successfully applied ten pairs exhibiting different phenotypes. Co-isolates from individual led robust, stable co-cultures, supporting theory cross-adaptation vivo. Investigation into VBB496 co-isolate pair revealed that had reduced antagonism, part due production secondary metabolites as well those Together, results indicate two-species system provides useful tool for exploring context infections.

Language: Английский

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Uncovering the GacS-mediated role in evolutionary progression through trajectory reconstruction in Pseudomonas aeruginosa

Nucleic Acids Research, Journal Year: 2024, Volume and Issue: 52(7), P. 3856 - 3869

Published: March 13, 2024

The genetic diversities of subpopulations drive the evolution pathogens and affect their ability to infect hosts cause diseases. However, most studies date have focused on identification characterization adaptive mutations in single colonies, which do not accurately reflect phenotypes an entire population. Here, identify composition variant within a pathogen population, we developed streamlined approach that combines high-throughput sequencing population cells with genotyping colonies. Using this method, reconstructed detailed quorum-sensing (QS) evolutionary trajectory Pseudomonas aeruginosa. Our results revealed new mutation gacS gene, codes for histidine kinase sensor two-component system (TCS), during QS evolution. This reduced activity, allowing sweep throughout whole while still being vulnerable invasion by emerging master regulator LasR-null mutants. By tracking trajectory, found facilitated QS-rewiring mutant. rapid revertant caused inactive GacS was be associated promotion ribosome biogenesis accompanied trade-off bacterial virulence host cells. In conclusion, our findings highlight crucial role global modulating progression

Language: Английский

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Structure‐preserving fixation allows scanning electron microscopy to reveal biofilm microstructure and interactions with immune cells

Journal of Microscopy, Journal Year: 2023, Volume and Issue: 293(1), P. 59 - 68

Published: Dec. 15, 2023

Pseudomonas aeruginosa is a pathogen that forms robust biofilms which are commonly associated with chronic infections and cannot be successfully cleared by the immune system. Neutrophils, most common white blood cells, target pathogen-killing mechanisms rendered largely ineffective protective physicochemical structure of biofilm. Visualisation complex interactions between cells will advance understanding how evade system could aid in developing treatment methods promote clearance minimal harm to host. Scanning electron microscopy (SEM) distinguishes itself as powerful, high-resolution tool for obtaining strikingly clear detailed topographical images. However, taking full advantage SEM's potential imaging requires fixation process simultaneously preserve both intricate biofilm architecture morphologies structural signatures characterising neutrophils responses at an infection site. Standard aldehyde-based techniques result significant loss matrix material responding thereby obscuring details matrix. Here we show improved technique using cationic dye alcian blue visualise neutrophil three-dimensional P. biofilms. We also demonstrate this better preserves structures grown from two other bacterial species, Klebsiella pneumoniae Burkholderia thailandensis.

Language: Английский

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Physiological Concentrations of Calcium Interact with Alginate and Extracellular DNA in the Matrices of Pseudomonas aeruginosa Biofilms to Impede Phagocytosis by Neutrophils

Langmuir, Journal Year: 2023, Volume and Issue: 39(48), P. 17050 - 17058

Published: Nov. 16, 2023

Biofilms are communities of interacting microbes embedded in a matrix polymer, protein, and other materials. develop distinct mechanical characteristics that depend on their predominant components. These components may be produced by themselves or, for infections vivo, incorporated from the host environment. Pseudomonas aeruginosa (P. aeruginosa) is human pathogen forms robust biofilms extensively tolerate antibiotics effectively evade clearance immune system. Two important bacterial-produced polymers matrices P. alginate extracellular DNA (eDNA), both which anionic therefore have potential to interact electrostatically with cations. Many physiological sites infection contain significant concentrations calcium ion (Ca2+). In this study, we investigate structural impacts Ca2+ supplementation alginate-dominated grown vitro, evaluate impact targeted enzyme treatments cells. We use multiple-particle tracking microrheology changes biofilm viscoelasticity caused treatment lyase or DNase I. For without Ca2+, correlate decrease relative elasticity increased phagocytic success. However, find growth disrupts correlation except case where enzymes applied. This suggests cation impacting microstructure nontrivial ways. Indeed, confocal laser scanning fluorescence microscopy electron reveal unique Ca2+-dependent eDNA microstructures. Our results suggest presence drives formation structurally compositionally discrete microdomains within through electrostatic interactions alginate. Further, observe these structures serve protective function as dissolution required render bacteria vulnerable phagocytosis neutrophils.

Language: Английский

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Proteomic approach to identify host cell attachment proteins provides protective Pseudomonas aeruginosa vaccine antigen FtsZ

npj Vaccines, Journal Year: 2024, Volume and Issue: 9(1)

Published: Oct. 28, 2024

Pseudomonas aeruginosa is an opportunistic Gram-negative pathogen that causes severe nosocomial infections in susceptible individuals due to the emergence of multidrug-resistant strains. There are no approved vaccines against P. nor candidates active clinical development, highlighting need for novel and strategies. Using a cell-blot proteomic approach, we reproducibly identified 49 proteins involved interactions with human lung epithelial cells across four Among these were cell division protein FtsZ outer membrane OpmH. Escherichia coli BL21 overexpressing recombinant or rOpmH showed 66- 15-fold increased ability attach 16HBE14o− cells, further supporting their involvement host attachment. Both antigens led proliferation NK CD8+ cytotoxic T significant increases production IFN-γ, IL-17A, TNF IL-4 immunised mice elicited strong antigen-specific serological IgG1 IgG2c responses. Immunisation significantly reduced bacterial burden lungs by 1.9-log CFU dissemination spleen 1.8-log CFU. The protective antigen candidate, FtsZ, would not have been traditional approaches relying on either virulence mechanisms sequence-based predictions, opening new avenues development anti-P. vaccine.

Language: Английский

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Phylogenomics of nontuberculous mycobacteria respiratory infections in people with cystic fibrosis

Paediatric Respiratory Reviews, Journal Year: 2023, Volume and Issue: 46, P. 63 - 70

Published: Feb. 10, 2023

Nontuberculous mycobacteria (NTM) can cause severe pulmonary disease in people with cystic fibrosis (pwCF). These infections present unique challenges for diagnosis and treatment, prompting a recent interest understanding NTM transmission pathogenesis during chronic infection. Major gaps remain our knowledge regarding basic pathogenesis, immune evasion strategies, population dynamics, recombination potential, the evolutionary implications of host antibiotic pressures long-term pwCF. Phylogenomic techniques have emerged as an important tool tracking global patterns are beginning to be used ask fundamental biological questions about adaptation pathogenesis. In this review, we discuss burden lung (NTM-LD), highlight use phylogenomics research, address clinical associated these studies.

Language: Английский

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