Antibacterial Efficacy of Phages against
            <i>Pseudomonas aeruginosa</i>
            Infections in Mice and
            <i>Drosophila melanogaster</i>

Heo, Yong; Lee, Yu-Rim; Jung, Hyun-Hee; Lee, Jung-Eun; Ko, GwangPyo; Cho, You‐Hee

doi:10.1128/aac.01646-08

Cited by 103 publications

(93 citation statements)

References 33 publications

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“…The rise of variants in the presence of lytic phage has been one of the foundations for evolution studies (18)(19)(20)(21)(22)(23)(24)(25); however, this is also one of the reasons why phage therapy has always been considered with skepticism by the medical community (26). The current rise of antibiotic-resistant bacteria is forcing researchers to look for alternative treatments, and phage therapy has proven to be promising in several animal case studies (27)(28)(29)(30)(31), as well as in human clinical trials (32,33). The emergence of phage-resistant variants is expected in many applications of phage therapy; therefore, the understanding of the evolutionary biology of bacterium-phage interactions, specifically, the characteristics of the resistant population, is of utmost importance for the successful use of phages.…”

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confidence: 99%

Predation in Homogeneous and Heterogeneous Phage Environments Affects Virulence Determinants of Pseudomonas aeruginosa

Hosseinidoust

Tufenkji

Ven

2013

Appl Environ Microbiol

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bThe rise of bacterial variants in the presence of lytic phages has been one of the basic grounds for evolution studies. However, there are incongruent results among different studies investigating the effect of phage resistance acquisition on bacterial fitness and virulence. We used experimental evolution to generate three classes of Pseudomonas aeruginosa variants under selective pressure from two different homogeneous phage environments and one heterogeneous phage environment. The fitness and virulence determinants of the variants, such as growth, motility, biofilm formation, resistance to oxidative stress, and the production of siderophores and chromophores, changed significantly compared to the control. Variants with similar colony morphology that were developed through different phage treatments have different phenotypic traits. Also, mRNA transcription for genes associated with certain phenotypic traits changed significantly; however, sequencing did not reveal any point mutations in selected gene loci. Furthermore, the appearance of small colony variants and melanogenic variants and the increase in pyocyanin and pyoverdin production for some variants are believed to affect the virulence of the population. The knowledge gained from this study will fundamentally contribute to our understanding of the evolutionary dynamics of bacteria under phage selective pressure which is crucial to the efficient utilization of bacteriophages in medical contexts. Pseudomonas aeruginosa is a metabolically versatile gammaproteobacterium which inhabits terrestrial, aquatic, animal, human, and plant host-associated environments (1). This pathogen is endowed with a fairly large genome (2) containing genes for many different virulence factors and regulatory mechanisms, allowing it to adapt to hostile environments (3). Moreover, changing environmental conditions result in rapid diversification of P. aeruginosa genotype to produce a range of morphologically distinct phenotypic variants (4, 5) through processes such as phase variation (6) and adaptive mutations (7). This adaptability is believed to give the variants a selective advantage under unfavorable conditions. Clinical isolates of Pseudomonas have been reported to display a high degree of phenotypic diversity (8-10), especially those isolated from antibiotic treated patients. As a result of its high adaptability (11) and intrinsic antibiotic resistance (12), infections caused by P. aeruginosa are, in many instances, difficult to eradicate and can become persistent or even chronic (10), earning this bacterium a reputation as a paradigm of bacterial resistance (13).By selecting for phage resistance, bacteriophages have been identified as agents that can drive the emergence of P. aeruginosa variants due to the strong selective pressure that they exert on the host community (14, 15). At an estimated total of 10 31 , bacteriophages are the most abundant biological agent on earth (16) and, based on their prevalence and effects on prokaryotic communities, they can play a significan...

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confidence: 99%

Predation in Homogeneous and Heterogeneous Phage Environments Affects Virulence Determinants of Pseudomonas aeruginosa

Hosseinidoust

Tufenkji

Ven

2013

Appl Environ Microbiol

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“…Bacteriophages, bacteria's natural predators, have proven to be promising in numerous animal case studies (9)(10)(11)(12)(13) and human clinical trials (14,15). One of the main fears concerning bacteriophage therapy is the potential for bacteriophage-induced bacterial genome evolution.…”

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Evolution of Pseudomonas aeruginosa Virulence as a Result of Phage Predation

Hosseinidoust

Ven

Tufenkji

2013

Appl Environ Microbiol

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The rapid increase in the emergence of antibiotic-resistant bacteria has attracted attention to bacteriophages for treating and preventing bacterial infections. Bacteriophages can drive the diversification of Pseudomonas aeruginosa, giving rise to phageresistant variants with different phenotypes from their ancestral hosts. In this study, we sought to investigate the effect of phage resistance on cytotoxicity of host populations toward cultured mammalian cells. The library of phage-resistant P. aeruginosa PAO1 variants used was developed previously via experimental evolution of an isogenic host population using phages PP7 and E79. Our results presented herein indicate that the phage-resistant variants developed in a heterogeneous phage environment exhibit a greater ability to impede metabolic action of cultured human keratinocytes and have a greater tendency to cause membrane damage even though they cannot invade the cells in large numbers. They also show a heightened resistance to phagocytosis by model murine macrophages. Furthermore, all isolates produced higher levels of at least one of the secreted virulence factors, namely, total proteases, elastase, phospholipase C, and hemolysins. Reverse transcription-quantitative PCR (RT-qPCR) revealed upregulation in the transcription of a number of genes associated with virulence of P. aeruginosa for the phage-resistant variants. The results of this study indicate a significant change in the in vitro virulence of P. aeruginosa following phage predation and highlight the need for caution in the selection and design of phages and phage cocktails for therapeutic use.

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“…Due to the emergence of multidrug-resistant P. aeruginosa strains, there is an urgent need for alternative antibacterial strategies to control P. aeruginosa infections. Phage therapy has been resurrected, as it has successfully treated experimental infections caused by P. aeruginosa in model animals (6). Hence, knowledge about the genetic diversity and antibacterial efficacy of P. aeruginosa phages needs to be explored.…”

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Complete Genome Sequence of Pseudomonas aeruginosa Siphophage MP1412

Bae

Chung

Sim

et al. 2012

J Virol

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We report the complete genome sequence of Pseudomonas aeruginosa siphophage MP1412, which displays synteny to those of P. aeruginosa phages M6 and YuA. However, the presence of two homing endonucleases of the GIY-YIG family is unique to MP1412, suggesting their unique role in the phage life cycle of the bacterial host. Pseudomonas aeruginosa is a notorious nosocomial pathogen and causes fatal infections in immunocompromised individuals (2,4,8). Due to the emergence of multidrug-resistant P. aeruginosa strains, there is an urgent need for alternative antibacterial strategies to control P. aeruginosa infections. Phage therapy has been resurrected, as it has successfully treated experimental infections caused by P. aeruginosa in model animals (6). Hence, knowledge about the genetic diversity and antibacterial efficacy of P. aeruginosa phages needs to be explored.A new phage (MP1412) was isolated from local sewage samples, forming distinguishable plaques on P. aeruginosa strain PAO1. Based on its virion structure, MP1412 is a Siphoviridae morphotype B2, like the previously characterized phages YuA and M6 (1, 3). It requires type IV pilus (TFP) for infection, but it could not infect P. aeruginosa strain PA14. To elucidate the phage genetic elements which are involved in the phage-host interaction and thus delineate the host spectra of these phages, we determined the complete genome sequence of MP1412.Genomic DNA of MP1412, prepared as described previously (5), was sequenced using the GS FLX Titanium by the local service provider (Macrogen, Seoul, South Korea). The data processing was performed using Roche GS FLX software (version 2.6), and the open reading frames (ORFs) were predicted using GeneMark software (7). A homology search and a conserved domain analysis were carried out using BLASTP (http://www.ncbi.nlm.nih.gov /blast), and the potential presence of tRNAs were scanned using the tRNAscan-SE program (9).Genomic analysis revealed that the 61,167-bp genome of MP1412 displays synteny to those of P. aeruginosa phages YuA (58,663 bp; GenBank accession number AM749441) and M6 (59,446 bp; GenBank accession number DQ163916), with 78 ORFs (gp01 to gp77 and gp60.1) and no tRNAs identified. Based on the homology, the genome of MP1412 can be divided into three functional regions: nucleotide metabolism and DNA synthesis (gp01 to gp23), host interaction (gp24 to gp44), and virion assembly and host lysis (gp45 to gp77). The presence of integrase (gp26) and a phage repressor (gp24) in the second region indicates that MP1412 undergoes a lysogenic cycle. MP1412 contains a GGDEF domain protein (gp43), which may function as diguanylate cyclase (DGC) to form cyclic di-GMP, a global second messenger controlling bacterial motility and sessility. Enhanced activity of DGC leading to an elevated cyclic di-GMP level plays an important role in the early stage of biofilm formation in P. aeruginosa (10). Unique to MP1412 is the presence of a hypothetical bacterial protein (gp46) and two homing DNA endonucleases (gp25 and gp53) of the GIY-Y...

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Antibacterial Efficacy of Phages against Pseudomonas aeruginosa Infections in Mice and Drosophila melanogaster

Cited by 103 publications

References 33 publications

Predation in Homogeneous and Heterogeneous Phage Environments Affects Virulence Determinants of Pseudomonas aeruginosa

Predation in Homogeneous and Heterogeneous Phage Environments Affects Virulence Determinants of Pseudomonas aeruginosa

Evolution of Pseudomonas aeruginosa Virulence as a Result of Phage Predation

Complete Genome Sequence of Pseudomonas aeruginosa Siphophage MP1412

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