Antibacterial efficacy of R-type pyocins against Pseudomonas aeruginosa on biofilms and in a murine model of acute lung infection

Redero, Mar; Aznar, Javier; Prieto, Ana I.

doi:10.1093/jac/dkaa121

Cited by 12 publications

(11 citation statements)

References 48 publications

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“…When the 32 clinical isolates were tested against the 32 isolated pyocins, none were able to lyse the source strain or those strains with the same serotype or ST. As previously described, variability in the susceptibility to the pyocins was observed between those isolates that shared ST and/or serotype and the same type of pyocin, probably due to the frequently observed mutations in the LPS genes in CF, affecting recognition by the RBP 3 , 29 , 30 . Pyocins have been considered potential alternatives to antibiotics, and several studies have demonstrated antimicrobial activity of pyocins alone or in combination with other antimicrobials and those sharing the LPS as target 13 , 22 , 23 , 31 , 32 .…”

Section: Discussionmentioning

confidence: 99%

Study of 32 new phage tail-like bacteriocins (pyocins) from a clinical collection of Pseudomonas aeruginosa and of their potential use as typing markers and antimicrobial agents

Blasco

Aledo

Ortiz-Cartagena

et al. 2023

Sci Rep

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Phage tail-like bacteriocins (PTLBs) are large proteomic structures similar to the tail phages. These structures function in bacterial competition by making pores in the membrane of their competitors. The PTLBs identified in Pseudomonas aeruginosa are known as R-type and F-type pyocins, which have a narrow spectrum of action. Their specificity is determined by the tail fiber and is closely related to the lipopolysaccharide type of the target competitor strain. In this study, the genome sequences of 32 clinical of P. aeruginosa clinical isolates were analysed to investigate the presence of R-type and F-type pyocins, and one was detected in all strains tested. The pyocins were classified into 4 groups on the basis of the tail fiber and also the homology, phylogeny and structure of the cluster components. A relationship was established between these groups and the sequence type and serotype of the strain of origin and finally the killing spectrum of the representative pyocins was determined showing a variable range of activity between 0 and 37.5%. The findings showed that these pyocins could potentially be used for typing of P. aeruginosa clinical isolates, on the basis of their genomic sequence and cluster structure, and also as antimicrobial agents.

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Section: Discussionmentioning

confidence: 99%

Study of 32 new phage tail-like bacteriocins (pyocins) from a clinical collection of Pseudomonas aeruginosa and of their potential use as typing markers and antimicrobial agents

Blasco

Aledo

Ortiz-Cartagena

et al. 2023

Sci Rep

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“…Overall our findings highlight that clinical populations of P. aeruginosa exhibit a heterogenous response to R-pyocins and that this likely extends to any antimicrobial that utilizes the LPS. A number of LPS- and saccharide-binding phage have been identified and tested as antimicrobials against P. aeruginosa (24, 102–108) and other types of LPS-specific antimicrobials, including R-pyocins, are also being considered as treatments (12, 13, 37, 38, 109, 110). Our work implies that treatment with alternative therapies utilizing the LPS may not eradicate strains within infections completely, potentially leading to highly resistant isolates taking over.…”

Section: Discussionmentioning

confidence: 99%

“…A strain may be susceptible or resistant to any variation of the different R types, but are generally thought to be resistant to the subtype they produce (19,20,42). R-pyocins have previously been explored as potential therapeutics (28,51,52), but little is known about their binding to target cell receptors, or their killing efficacy in heterogenous populations of P. aeruginosa. It is known that multiple isolates sourced from populations of P. aeruginosa from CF lungs exhibit considerable variation in susceptibility to antibiotics (2,15,(53)(54)(55)(56), however heterogeneity in R-pyocin susceptibility, or susceptibility to other types of bacteriocins has not been explored.…”

Section: Introductionmentioning

confidence: 99%

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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“…Overall, our findings highlight that clinical populations of P. aeruginosa exhibit a heterogenous response to R-pyocins and that this likely extends to any antimicrobial that utilizes the LPS. A number of LPS-and saccharide-binding phage have been identified and tested as antimicrobials against P. aeruginosa (24,(92)(93)(94)(95)(96)(97)(98), and other types of LPS-specific antimicrobials, including R-pyocins, are also being considered as therapeutics (12,13,37,38,99,100). Our work implies that treatment with alternative therapies utilizing the LPS will not eradicate strains within infections completely, potentially leading to highly resistant isolates taking over.…”

Section: Figmentioning

confidence: 99%

“…Several monosaccharide residues on the outer core of the LPS have been proposed to confer susceptibility and specificity to some of the R-pyocin types (24,25); however, only the receptor of the R3-type pyocin has been clearly defined to be the Glc IV terminal glucose on the outer core of the LPS (26). R-pyocins have previously been explored as potential therapeutics (12,13,37,38), but little is known about their binding to target cells or their killing efficacy in heterogeneous P. aeruginosa populations.…”

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confidence: 99%

Heterogenous Susceptibility to R-Pyocins in Populations of Pseudomonas aeruginosa Sourced from Cystic Fibrosis Lungs

Mei

Thomas

Diggle

2021

mBio

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Bacteriocins are proteinaceous antimicrobials produced by bacteria that are active against other strains of the same species. R-type pyocins are phage tail-like bacteriocins produced by Pseudomonas aeruginosa. Due to their antipseudomonal activity, R-pyocins have potential as therapeutics in infection. P. aeruginosa is a Gram-negative opportunistic pathogen and is particularly problematic for individuals with cystic fibrosis (CF). P. aeruginosa organisms from CF lung infections develop increasing resistance to antibiotics, making new treatment approaches essential. P. aeruginosa populations become phenotypically and genotypically diverse during infection; however, little is known of the efficacy of R-pyocins against heterogeneous populations. R-pyocins vary by subtype (R1 to R5), distinguished by binding to different residues on the lipopolysaccharide (LPS). Each type varies in killing spectrum, and each strain produces only one R-type. To evaluate the prevalence of different R-types, we screened P. aeruginosa strains from the International Pseudomonas Consortium Database (IPCD) and from our biobank of CF strains. We found that (i) R1-types were the most prevalent R-type among strains from respiratory sources, (ii) a large number of strains lack R-pyocin genes, and (iii) isolates collected from the same patient have the same R-type. We then assessed the impact of intrastrain diversity on R-pyocin susceptibility and found a heterogenous response to R-pyocins within populations, likely due to differences in the LPS core. Our work reveals that heterogeneous populations of microbes exhibit variable susceptibility to R-pyocins and highlights that there is likely heterogeneity in response to other types of LPS-binding antimicrobials, including phage. IMPORTANCE R-pyocins have potential as alternative therapeutics against Pseudomonas aeruginosa in chronic infection; however, little is known about the efficacy of R-pyocins in heterogeneous bacterial populations. P. aeruginosa is known to become resistant to multiple antibiotics and to evolve phenotypic and genotypic diversity over time; thus, it is particularly difficult to eradicate in chronic cystic fibrosis (CF) lung infections. In this study, we found that P. aeruginosa populations from CF lungs maintain the same R-pyocin genotype but exhibit heterogeneity in susceptibility to R-pyocins from other strains. Our findings suggest there is heterogeneity in response to other types of LPS-binding antimicrobials, such as phage, highlighting the necessity of further studying the potential of LPS-binding antimicrobial particles as alternative therapies in chronic infections.

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Antibacterial efficacy of R-type pyocins against Pseudomonas aeruginosa on biofilms and in a murine model of acute lung infection

Cited by 12 publications

References 48 publications

Study of 32 new phage tail-like bacteriocins (pyocins) from a clinical collection of Pseudomonas aeruginosa and of their potential use as typing markers and antimicrobial agents

Study of 32 new phage tail-like bacteriocins (pyocins) from a clinical collection of Pseudomonas aeruginosa and of their potential use as typing markers and antimicrobial agents

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

Heterogenous Susceptibility to R-Pyocins in Populations of Pseudomonas aeruginosa Sourced from Cystic Fibrosis Lungs

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