Virulence reduction in bacteriophage resistant bacteria

León, Marcela; Bastías, Roberto

doi:10.3389/fmicb.2015.00343

Cited by 195 publications

(158 citation statements)

References 80 publications

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“…It would be interesting to know whether new variants emerge in such experiments. Alternatively, some phages driving evolution toward loss of virulence could be favoured if they exist (Leó n & Bastías, 2015). Another concern is the potential role of phages in horizontal transfer, which could be favoured by the longterm maintenance of phage genomes inside the bacteria during pseudolysogeny.…”

Section: Cross-resistance and Reversibility Of Mutantsmentioning

confidence: 99%

Pseudolysogeny and sequential mutations build multiresistance to virulent bacteriophages in Pseudomonas aeruginosa

Latino

2016

Microbiology

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Coevolution between bacteriophages (phages) and their prey is the result of mutualistic interactions. Here, we show that pseudolysogeny is a frequent outcome of infection by virulent phages of Pseudomonas aeruginosa and that selection of resistant bacterial mutants is favoured by continuous production of phages. We investigated the frequency and characteristics of P. aeruginosa strain PAO1 variants resisting infection by different combinations of virulent phages belonging to four genera. The frequency of resistant bacteria was 10 25 for single phage infection and 10 26 for infections with combinations of two or four phages. The genome of 27 variants was sequenced and the comparison with the genome of the parental PAO1 strain allowed the identification of point mutations or small indels. Four additional variants were characterized by a candidate gene approach. In total, 27 independent mutations were observed affecting 14 genes and a regulatory region. The mutations affected genes involved in biosynthesis of type IV pilus, alginate, LPS and O-antigen. Half of the variants possessed changes in homopolymer tracts responsible for frameshift mutations and these phase variation mutants were shown to be unstable. Eleven double mutants were detected. The presence of free phage DNA was observed in association with exclusion of superinfection in half of the variants and no chromosomal mutation could be found in three of them. Upon further growth of these pseudolysogens, some variants with new chromosomal mutations were recovered, presumably due to continuous evolutionary pressure.

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Section: Cross-resistance and Reversibility Of Mutantsmentioning

confidence: 99%

Pseudolysogeny and sequential mutations build multiresistance to virulent bacteriophages in Pseudomonas aeruginosa

Latino

2016

Microbiology

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“…It has been shown that phage-resistant bacteria lose their virulence during phage therapy (48). In contrast, the virulence of the bacteria may be increased with exposure to phage, according to this study.…”

Section: Resultsmentioning

confidence: 66%

Analyses of Short-Term Antagonistic Evolution of Pseudomonas aeruginosa Strain PAO1 and Phage KPP22 (Myoviridae Family, PB1-Like Virus Genus)

Uchiyama

Suzuki

Nishifuji

et al. 2016

Appl Environ Microbiol

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Pseudomonas aeruginosa causes serious intractable infections in humans and animals. Bacteriophage (phage) therapy has been applied to treat P. aeruginosa infections, and phages belonging to the PB1-like virus genus in the Myoviridae family have been used as therapeutic phages. To achieve safer and more effective phage therapy, the use of preadapted phages is proposed. To understand in detail such phage preadaptation, the short-term antagonistic evolution of bacteria and phages should be studied. In this study, the short-term antagonistic evolution of bacteria and PB1-like phage was examined by studying phage-resistant clones of P. aeruginosa strain PAO1 and mutant PB1-like phages that had recovered their infectivity. First, phage KPP22 was isolated and characterized; it was classified as belonging to the PB1-like virus genus in the Myoviridae family. Subsequently, three KPP22-resistant PAO1 clones and three KPP22 mutant phages capable of infecting these clones were isolated in three sets of in vitro experiments. It was shown that the bacterial resistance to phage KPP22 was caused by significant decreases in phage adsorption and that the improved infectivity of KPP22 mutant phages was caused by significant increases in phage adsorption. The KPP22-resistant PAO1 clones and the KPP22 mutant phages were then analyzed genetically. All three KPP22-resistant PAO1 clones, which were deficient for the O5 antigen, had a common nonsense mutation in the wzy gene. All the KPP22 mutant phage genomes showed the same four missense mutations in the open reading frames orf060, orf065, and orf086. The information obtained in this study should be useful for further development of safe and efficient phage therapy. IMPORTANCEPseudomonas aeruginosa causes serious intractable infections in humans and animals; bacteriophage (phage) therapy has been utilized to treat P. aeruginosa infections, and phages that belong to the PB1-like virus genus in the family Myoviridae have been used as therapeutic phages. The preadapted phage is trained in advance through the antagonistic evolution of bacteria and phage and is proposed to be used to achieve safer and more effective phage therapy. In this study, to understand the phage preadaptation, the in vitro short-term antagonistic evolution was studied using P. aeruginosa strain PAO1 and the newly isolated PB1-like phage KPP22. Phage KPP22 was characterized, and the molecular framework regarding the phage preadaptation of KPP22 was elucidated. The importance of study of antagonistic evolution of bacteria and phage in phage therapy is discussed.

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“…Phage resistance most commonly develops through the down-regulation, shielding, or modification of bacterial cell surface receptors required for viral attachment [69,70]. To ensure survival, evolved phages tend to bind to highly conserved surface receptors, such as those required for virulence [71][72][73].…”

Section: Phage Resistancementioning

confidence: 99%

“…In addition, phage resistance is not always detrimental to treatment, because in many cases acquired resistance is costly for the bacterium (e.g. loss of virulence toward their hosts, lower growth rate, decreased lifespan, or loss of the ability to attach or invade to mammalian cells) [70,71,73,75]. In addition, acquiring phage resistance can cause bacteria to become more antibiotic-sensitive [76,77].…”

Section: Phage Resistancementioning

confidence: 99%

Phage therapy: awakening a sleeping giant

Roach

Debarbieux

2017

Emerging Topics in Life Sciences

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Correspondence: Laurent Debarbieux (laurent.debarbieux@pasteur.fr)For a century, bacterial viruses called bacteriophages have been exploited as natural antibacterial agents. However, their medicinal potential has not yet been exploited due to readily available and effective antibiotics. After years of extensive use, both properly and improperly, antibiotic-resistant bacteria are becoming more prominent and represent a worldwide public health threat. Most importantly, new antibiotics are not progressing at the same rate as the emergence of resistance. The therapeutic modality of bacteriophages, called phage therapy, offers a clinical option to combat bacteria associated with diseases. Here, we discuss traditional phage therapy approaches, as well as how synthetic biology has allowed for the creation of designer phages for new clinical applications. To implement these technologies, several key aspects and challenges still need to be addressed, such as narrow spectrum, safety, and bacterial resistance. We will summarize our current understanding of how phage treatment elicits mammalian host immune responses, as well bacterial phage resistance development, and the potential impact each will have on phage therapy effectiveness. We conclude by discussing the need for a paradigm shift on how phage therapy strategies are developed.

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Virulence reduction in bacteriophage resistant bacteria

Cited by 195 publications

References 80 publications

Pseudolysogeny and sequential mutations build multiresistance to virulent bacteriophages in Pseudomonas aeruginosa

Pseudolysogeny and sequential mutations build multiresistance to virulent bacteriophages in Pseudomonas aeruginosa

Analyses of Short-Term Antagonistic Evolution of Pseudomonas aeruginosa Strain PAO1 and Phage KPP22 (Myoviridae Family, PB1-Like Virus Genus)

Phage therapy: awakening a sleeping giant

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