Susceptibility to R-pyocins of Pseudomonas aeruginosa clinical isolates from cystic fibrosis patients

Redero, Mar; López-Causapé, Carla; Aznar, Javier; Oliver, Antonio; Blázquez, Jesús; Prieto, Ana I.

doi:10.1093/jac/dky261

Cited by 23 publications

(27 citation statements)

References 39 publications

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“…While we expect that some strains may in fact produce R-pyocins but were unable to be typed due to sequencing or contig errors, it is possible that many of these strains may not possess R-pyocins at all. Another group evaluating R-pyocin susceptibility among 34 CF isolates found that 23 (68%) of their isolates did not produce R-pyocins or could not be typed (69). This suggests that CF isolates of P. aeruginosa may lose the ability to produce R-pyocins later in chronic infection, but more work is necessary to confirm this phenotype and explore the potential fitness advantages of this evolutionary trajectory.…”

Section: Discussionmentioning

confidence: 99%

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Heterogenous susceptibility to R-pyocins in populations ofPseudomonas aeruginosasourced from cystic fibrosis lungs

Mei

Thomas

Diggle

2020

Preprint

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Pseudomonas aeruginosa is a Gram-negative opportunistic pathogen and a major determinant of declining lung function in individuals with cystic fibrosis (CF). P. aeruginosa possesses many intrinsic antibiotic resistance mechanisms, and isolates from chronic CF lung infections develop increasing resistance to multiple antibiotics over time, making new treatment approaches necessary. R-type pyocins are narrow spectrum, phage tail-like bacteriocins, specifically produced by P. aeruginosa to kill other strains of P. aeruginosa. Due to their specific anti-pseudomonal activity and similarity to bacteriophage, R-pyocins have potential as additional therapeutics against P. aeruginosa, either in isolation, in combination with antibiotics, or as an alternative to phage therapy. While it is increasingly acknowledged that colonizing P. aeruginosa populations become both phenotypically and genetically diverse during chronic infection of the CF lung, little is known about the efficacy of R-pyocins against heterogenous populations of P. aeruginosa. To investigate this, we first evaluated the distribution of R-pyocin subtypes in different environments, by bioinformatically R-pyocin typing single strains from the International Pseudomonas Consortium Database (IPCD). We found that R1-type pyocins are the most prevalent across strains from all environments, including those sourced from CF. We corroborated these findings by R-pyocin typing whole populations of CF strains from our own biobank of isolates sourced from expectorated CF sputum and found that (i) R1-pyocins were the most prevalent R-type among our CF strains and (ii) isolates of P. aeruginosa from whole populations collected from the same patient have the same R-pyocin type. Moreover, we found heterogeneity in susceptibility to R-pyocins within populations of P. aeruginosa, which is likely due to differences in the lipopolysaccharide (LPS), supporting the idea that the core of the LPS is the receptor for R-pyocins. Our findings suggest there is likely heterogeneity in response to other types of LPS-binding antimicrobials, such as phage, and increases our understanding of the potential of bacteriophage and other phage-like, LPS-binding antimicrobial particles as novel alternative therapies in CF.ImportanceP. aeruginosa possesses many intrinsic antibiotic resistance mechanisms and isolates from chronic cystic fibrosis (CF) lung infections become resistant to multiple antibiotics over time, making new treatment approaches necessary. R-pyocins have potential as additional therapeutics against P. aeruginosa, however little is known about the efficacy and heterogeneity in resistance to R-pyocins in whole populations of P. aeruginosa, particularly diverse P. aeruginosa sourced from chronic CF lung infections. It is believed that in the CF lung, one strain of P. aeruginosa dominates and diversifies over the course of infection. Mechanistic explanations for this single strain domination are sparse, however, R-pyocins could play a key role given their strain-specificity and antimicrobial properties. In this study, we have found that P. aeruginosa populations of the same R-pyocin type exhibit heterogeneity in susceptibility to R-pyocins from other strains. Our findings suggest there is likely heterogeneity in response to other types of LPS-binding antimicrobials, including phage, and highlights the necessity of further studying the potential of LPS-binding antimicrobial particles as alternative therapies in CF and chronic infection.

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Section: Discussionmentioning

confidence: 99%

“…Previous studies have R-pyocin typed single isolates of P. aeruginosa from CF patients and compared R-types from longitudinal collections of single isolates (58,69). The typing of single isolates does not consider the genotypic and phenotypic diversity of P. aeruginosa which evolves over the course of chronic infection (2-4, 10-12, 14-16).…”

Section: Discussionmentioning

confidence: 99%

Heterogenous susceptibility to R-pyocins in populations ofPseudomonas aeruginosasourced from cystic fibrosis lungs

Mei

Thomas

Diggle

2020

Preprint

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“…These bacteriocins often possess a narrow spectrum of antimicrobial activity against closely related strains and so are likely to be involved in interstrain competition. Recently it has been shown that strains of P. aeruginosa isolated from CF lungs are particularly susceptible to R-pyocins, mainly due to their LPS architecture with nontypeable or non-accessible O-serotypes (22).…”

Section: Discussionmentioning

confidence: 99%

Competition in biofilms between cystic fibrosis isolates ofPseudomonas aeruginosais shaped by R-pyocins

Oluyombo

Diggle

Penfold

2018

Preprint

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Pseudomonas aeruginosa is an opportunistic pathogen responsible for a number of different human infections and is the leading cause of morbidity and mortality in cystic fibrosis (CF) patients. P. aeruginosa infections are difficult to treat due to a number of antibiotic resistance mechanisms and the organisms propensity to form multicellular biofilms. Epidemic strains of P. aeruginosa often dominate within the lungs of individual CF patients, but how they achieve this is poorly understood. One of the ways strains of P. aeruginosa can compete, is by producing chromosomally encoded bacteriocins, called pyocins. Three major classes of pyocin have been identified in P. aeruginosa: soluble pyocins (S-types) and tailocins (R-and F-types). In this study, we investigated the distribution of S-and R-type pyocins in 24 clinical strains isolated from individual CF patients and then focused on understanding their roles on inter-strain competition. We found that (i) each strain produced only one R-pyocin type, but the number of S-pyocins varied between strains; (ii) R-pyocins were generally important for strain dominance during competition assays in planktonic cultures and biofilm communities in strains with both disparate R and S pyocin sub-types. (iii) purified R-pyocins demonstrated significant antimicrobial activity against established biofilms. Our work provides support for a key role played by R-pyocins in the competition between P. aeruginosa strains, and may help explain why certain strains and lineages of P. aeruginosa dominate and displace others during CF lung infection. Furthermore, we demonstrate the potential of exploiting Rpyocins for therapeutic gains in an era when antibiotic resistance is a global concern. IMPORTANCE. A major clinical problem caused by Pseudomonas aeruginosa, is chronic biofilm infection of the lungs in individuals with cystic fibrosis (CF). Epidemic P. aeruginosa strains dominate and displace others during CF infection, but these intra-species interactions remain poorly understood. Here we demonstrate that R-pyocins (bacterocins) are important factors in driving competitive interactions in biofilms between P. aeruginosa strains isolated from different CF patients. In addition, we found that these phage-like pyocins are inhibitory against mature biofilms of susceptible strains. This highlights the potential of Rpyocins as antimicrobial and antibiofilm agents, at a time when new antimicrobial therapies are desperately needed.

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“…O antigen likely also protects P. aeruginosa from the killing effects of S pyocins since studies in enterics have shown that the O antigen chain length and density are important factors in protecting them against colicins [160][161][162]. Interestingly, since a high proportion of CF isolates are susceptible to at least one subtype of R pyocin, the use of pyocin cocktails could potentially be viewed as highly targeted therapeutics to treat chronic infections in CF patients [163]. Indeed, the efficacy of a number of pyocins has been demonstrated in in vivo animal models [164][165][166][167].…”

Section: Phages and Pyocinsmentioning

confidence: 99%

The Role of Pseudomonas aeruginosa Lipopolysaccharide in Bacterial Pathogenesis and Physiology

2019

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The major constituent of the outer membrane of Gram-negative bacteria is lipopolysaccharide (LPS), which is comprised of lipid A, core oligosaccharide, and O antigen, which is a long polysaccharide chain extending into the extracellular environment. Due to the localization of LPS, it is a key molecule on the bacterial cell wall that is recognized by the host to deploy an immune defence in order to neutralize invading pathogens. However, LPS also promotes bacterial survival in a host environment by protecting the bacteria from these threats. This review explores the relationship between the different LPS glycoforms of the opportunistic pathogen Pseudomonas aeruginosa and the ability of this organism to cause persistent infections, especially in the genetic disease cystic fibrosis. We also discuss the role of LPS in facilitating biofilm formation, antibiotic resistance, and how LPS may be targeted by new antimicrobial therapies.

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Susceptibility to R-pyocins of Pseudomonas aeruginosa clinical isolates from cystic fibrosis patients

Abstract: Our results highlight the possibility of using R-pyocins as therapeutic agents, alone or as adjuvants, against P. aeruginosa in cystic fibrosis.

Cited by 23 publications

References 39 publications

Heterogenous susceptibility to R-pyocins in populations ofPseudomonas aeruginosasourced from cystic fibrosis lungs

Heterogenous susceptibility to R-pyocins in populations ofPseudomonas aeruginosasourced from cystic fibrosis lungs

Competition in biofilms between cystic fibrosis isolates ofPseudomonas aeruginosais shaped by R-pyocins

The Role of Pseudomonas aeruginosa Lipopolysaccharide in Bacterial Pathogenesis and Physiology

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