R-pyocins as targeted antimicrobials against Pseudomonas aeruginosa

npj Antimicrobials and Resistance, Год журнала: 2025, Номер 3(1)

Опубликована: Фев. 28, 2025

R-pyocins, bacteriocin-like proteins produced by Pseudomonas aeruginosa, present a promising alternative to phage therapy and/or adjunct currently used antimicrobials in treating bacterial infections due their targeted specificity, lack of replication, and stability. This review explores the structural, mechanistic, therapeutic aspects including potential for chronic infection management, discusses recent advances delivery methods, paving way novel antimicrobial applications clinical settings.

Язык: Английский

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Impact of CFTR Modulation on Pseudomonas aeruginosa Infection in People With Cystic Fibrosis

The Journal of Infectious Diseases, Год журнала: 2024, Номер 230(3), С. e536 - e547

Опубликована: Март 5, 2024

Abstract Background Pseudomonas aeruginosa is a multidrug-resistant pathogen causing recalcitrant pulmonary infections in people with cystic fibrosis (pwCF). Cystic transmembrane conductance regulator (CFTR) modulators have been developed that partially correct the defective chloride channel driving disease. Despite many clinical benefits, studies adults demonstrated while P. sputum load decreases, chronic infection persists. Here, we investigate how pwCF may change altered lung environment after CFTR modulation. Methods strains (n = 105) were isolated from of 11 chronically colonized at baseline and up to 21 months posttreatment elexacaftor-tezacaftor-ivacaftor or tezacaftor-ivacaftor. Phenotypic characterization comparative genomics performed. Results Clonal lineages persisted therapy, no evidence displacement by alternative strains. We identified commonly mutated genes among patient isolates be positively selected for CFTR-modulated lung. However, classic phenotypes such as mucoid morphology sustained, remained just resistant clinically relevant antibiotics. Conclusions benefits modulators, clonal persist prove difficult manage future, especially advanced

Язык: Английский

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Mucus polymer concentration and in vivo adaptation converge to define the antibiotic response of Pseudomonas aeruginosa during chronic lung infection

mBio, Год журнала: 2024, Номер 15(6)

Опубликована: Апрель 23, 2024

The airway milieu of individuals with muco-obstructive diseases (MADs) is defined by the accumulation dehydrated mucus due to hyperabsorption surface liquid and defective mucociliary clearance. Pathological becomes progressively more viscous age disease severity concentration overproduction mucin host-derived extracellular DNA (eDNA). Respiratory MADs provides a niche for recurrent persistent colonization respiratory pathogens, including

Язык: Английский

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Pseudomonas superinfection drives Pf phage transmission within airway infections in patients with cystic fibrosis

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Янв. 15, 2025

Pf bacteriophages, lysogenic viruses that infect Pseudomonas aeruginosa (Pa), are implicated in the pathogenesis of chronic Pa infections; phage-infected (Pf+) strains known to predominate people with cystic fibrosis (pwCF) who older and have more severe disease. However, transmission patterns underlying progressive dominance Pf+ unclear. In particular, it is unknown whether phage commonly occurs horizontally between bacteria within airway via viral particles or if mostly acquired new infections. Here, we studied genomic sequences from 3 patient cohorts totaling 663 clinical isolates 105 pwCF. We identify analyze patients genetically similar groups called "clone types". find predominantly passed down vertically lineages rarely horizontal transfer clone types airway. Conversely, extensive evidence superinfection by a new, distinct Pf+. Finally, show reduced activity type IV pilus susceptibility vitro. These results cast light on virulence-associated phages setting.

Язык: Английский

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Evolutionary Rescue Promotes Mutators

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2025, Номер unknown

Опубликована: Фев. 15, 2025

Abstract The role of mutation rate in evolutionary rescue has been extensively explored, but little work investigated how can promote mutators, lineages with higher rates. We investigate the likelihood on a mutator background that either emerges de novo or pre-exists population prior to severe environmental change. If such an event occurs, lineage sweeps into population, and thus stress promoted mutators. Our findings indicate evolution substantially boost probabilities, stronger mutators are most effective when wildtype low rate, while their advantage diminishes for Interestingly, at intermediate rates, emerging be almost equally likely sweep no matter slowly quickly environment changes. However, only very slow changes due sequential nature necessary mutations occur. Finally, we show pre-existing significantly more compared wildtype, provided wildtype’s is relatively low. This research opens new avenues investigating dynamics response stress.

Язык: Английский

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Fitness trade-off and the discovery of a novel missense mutation in the PmrB sensor kinase of a colistin-resistant Pseudomonas aeruginosa strain developed by adaptive laboratory evolution

Microbial Pathogenesis, Год журнала: 2025, Номер unknown, С. 107473 - 107473

Опубликована: Март 1, 2025

Язык: Английский

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Flagellar motility and the mucus environment influence aggregation-mediated antibiotic tolerance of Pseudomonas aeruginosa in chronic lung infection

mBio, Год журнала: 2025, Номер unknown

Опубликована: Май 15, 2025

ABSTRACT Pseudomonas aeruginosa routinely causes chronic lung infection in individuals with muco-obstructive airway diseases (MADs). In MADs, P. forms antibiotic-tolerant biofilm-like aggregates within hyperconcentrated mucus. While the contribution of mucin hyper-concentration to antibiotic tolerance and bacterial aggregation has been described, less is known about factors involved. We previously found that populations isolated from people MADs exhibited significant variability tolerance. This not explained by resistance or mucus environment, suggesting bacterial-driven mechanisms play a crucial role treatment outcomes. Here, we investigated flagellar motility aggregate formation manipulating behaviors. Similar prior studies, loss resulted increased various antibiotics. identified novel differential roles MotAB MotCD stators, which power rotation, antimicrobial formation. addition, control fliC expression was important for Constitutive allowed overcome entropic forces mucin, antagonizing increasing efficacy. Lastly, demonstrate neutrophil elastase, an abundant protease infection, promotes failure impairing leading These results underscore tolerance, enhancing our understanding how adapts environment . IMPORTANCE Antibiotic key driver mortality The contribute MADS are poorly understood. impact swimming behaviors on context diseased environment. Loss motility, common adaptation drives promoting under physiologically relevant concentrations. uncovered stators Furthermore, host-derived protease, motility. further airway, revealing potential new targets improve infection.

Язык: Английский

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Pseudomonas aeruginosa: ecology, evolution, pathogenesis and antimicrobial susceptibility

Nature Reviews Microbiology, Год журнала: 2025, Номер unknown

Опубликована: Май 29, 2025

Язык: Английский

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Pseudomonas aeruginosa Lipid A Structural Variants Induce Altered Immune Responses

American Journal of Respiratory Cell and Molecular Biology, Год журнала: 2024, Номер 71(2), С. 207 - 218

Опубликована: Апрель 24, 2024

causes chronic lung infection in cystic fibrosis (CF), resulting structural damage and progressive pulmonary decline.

Язык: Английский

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Variation in the response to antibiotics and life-history across the major Pseudomonas aeruginosa clone type (mPact) panel

Microbiology Spectrum, Год журнала: 2024, Номер 12(7)

Опубликована: Июнь 11, 2024

Pseudomonas aeruginosa is a ubiquitous, opportunistic human pathogen. Since it often expresses multidrug resistance, new treatment options are urgently required. Such treatments usually assessed with one of the canonical laboratory strains, PAO1 or PA14. However, these two strains unlikely representative infecting patients, because they have adapted to conditions and do not capture enormous genomic diversity species. Here, we characterized major P. clone type (mPact) panel. This panel consists 20 which reflect species' diversity, cover all types, both patient environmental origins. We found significant strain variation in distinct responses toward antibiotics general growth characteristics. Only few measured traits related, suggesting independent trait optimization across strains. High resistance levels were only identified for clinical mPact isolates could be linked known antimicrobial (AMR) genes. One strain, H01, produced highly unstable AMR combined reduced under drug-free conditions, indicating an evolutionary cost resistance. The expression microcolonies was common among especially H15, also showed growth, possibly another trade-off. By linking isolation source, virulence life history traits, further specific adaptive strategies individual either host processes degradation pathways. Overall, provides reasonably sized set enabling in-depth analysis designs dynamics consideration diversity. New needed high-risk pathogens such as multidrug-resistant pathogen aeruginosa. characterize It different origins that types species well its shows (i) against antibiotics, including several last resort antibiotics; (ii) related associated response (iii) developed novel approach integrates information on virulence, life-history characteristics, allowing us demonstrate presence focus interaction resource processing. In conclusion, manageable number this important analyses dynamics.

Язык: Английский

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