Targeting mechanisms of tailed bacteriophages

Nóbrega, Franklin L.; Vlot, Marnix; Jonge, Patrick A. de; Dreesens, Lisa L.; Beaumont, Hubertus J. E.; Lavigne, Rob; Dutilh, Bas E.; Brouns, Stan J. J.

doi:10.1038/s41579-018-0070-8

Cited by 369 publications

(362 citation statements)

References 184 publications

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“…The positive correlation between phage resistance and reduced virulence has been previously observed in the adaptive interplay between Klebsiella and its bacteriophages, with the isolation of less virulent bacterial mutants, and may be an expected trade-off in their evolutionary arms race (50). It is therefore not surprising that co-evolution of specific phage with this host resulted in the narrow host ranges observed in this study, a characteristic that could be exploited for therapeutic purposes, as specific recognition by phage receptors (tail spikes) of complementary anti-receptors on the host cell surface is at the core of phage lytic activity (51,52).…”

Section: Discussionmentioning

confidence: 88%

“…AmPh_EK29) and must also be considered when designing optimal therapeutic mixes. Variability in the lipid A core of the LPS surface layer could also contribute phage resistance in JIE4282, as this is generally highly conserved within K. pneumoniae , making it an important determinant for host receptor recognition (51,52). Other differences (lack of fimbrial locus in JIE4046, different plasmid content (JIE4005, 4019 and 4020), ompK36 variants etc.)…”

Section: Discussionmentioning

confidence: 99%

“…seemed not to directly impact the susceptibility patterns to most of the tested phages. However, these all have the potential to affect viral host range and synergy when phages are to be used for therapeutic cocktails preparation (51,52).…”

Section: Discussionmentioning

confidence: 99%

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K. pneumoniaeST258 genomic variability and bacteriophage susceptibility

Venturini

Zakour

Bowring

et al. 2019

Preprint

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24Multidrug resistant carbapenemase-producing Klebsiella pneumoniae capable of causing 25 severe disease in humans is classified as an urgent threat by health agencies worldwide. 26 Bacteriophages are being actively explored as potential therapeutics against these multidrug 27 resistant pathogens. We are currently developing bacteriophage therapy against carbepenem-28 resistant K. pneumoniae belonging to the genetically diverse, globally disseminated clonal 29 group CG258. In an effort to define a robust experimental approach for effective selection of 30 lytic viruses for therapy, we have fully characterized the bacterial genomes of 18 target 31 strains, tested them against novel lytic bacteriophages, and generated phage-susceptibility 32 profiles. The genomes of K. pneumoniae isolates carrying blaNDM and blaKPC were sequenced 33 and isolates belonging to CG258 were selected for susceptibility testing using a panel of lytic 34 bacteriophages (n=65). The local K. pneumoniae CG258 population was dominated by 35 isolates belonging to sequence type ST258 clade 1 (86%). The primary differences between 36 ST258 genomes were variations in the capsular locus (cps) and in prophage content. We 37 showed that CG258-specific lytic phages primarily target the capsule, and that successful 38 infection is blocked in many, post-adsorption, by immunity conferred by existing prophages. 39Five bacteriophages specifically active against K. pneumoniae ST258 clade 1 (n=5) 40 belonging to the Caudovirales order were selected for further characterization. Our findings 41 show that effective control of K. pneumoniae CG258 with phage will require mixes of 42 diverse lytic viruses targeting all relevant cps variants and allowing for variable prophage 43 content. These insights will facilitate identification and selection of therapeutic phage 44 candidates against this serious pathogen. 45 46 47 48 Importance 49Bacteriophages are natural agents that exclusively and selectively kill bacteria and have the 50 potential to be useful in the treatment of multidrug resistant infections. K. pneumoniae 51 CG258 is a main agent of life-threatening sepsis that is often resistant to last-line antibiotics. 52Our work highlights some key requirements for developing bacteriophage preparations 53 targeting this pathogen. By defining the genomic profile of our clinical K. pneumoniae 54 CG258 population and matching it with bacteriophage susceptibility patterns, we found that 55 bacteriophage ability to lyse each strain correlates well with K. pneumoniae CG258 structural 56 subtypes (capsule variants). This indicates that preparation of bacteriophage therapeutics 57 targeting this pathogen should aim at including phages against each bacterial capsular 58 subtype. This necessitates a detailed understanding of the diversity of circulating isolates in 59 different geographical areas in order to make rational therapeutic choices. 60 61 62 Klebsiella pneumoniae is an important ubiquitous Gram-negative species capable of causing 63 disease in both humans an...

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Section: Discussionmentioning

confidence: 88%

Section: Discussionmentioning

confidence: 99%

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K. pneumoniaeST258 genomic variability and bacteriophage susceptibility

Venturini

Zakour

Bowring

et al. 2019

Preprint

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“…Bacterial sensitivity/resistance to phages is typically characterized using phenotypic methods such as cross-infection patterns against a panel of phages [14][15][16][17][18][19][20][21][22][23][24][25][26][27] or by whole-genome sequencing of phage-resistant mutants [28][29][30][31][32]. As such, our understanding of bacterial resistance mechanisms against phages remains limited, and the field is therefore in need of improved methods to characterize phage-host interactions, determine the generality and diversity of phage resistance mechanisms in nature, and identify the degree of specificity for each bacterial resistance mechanism across diverse phage types [13,25,26,[33][34][35][36][37][38][39][40][41][42][43][44][45][46][47].…”

Section: Introductionmentioning

confidence: 99%

High-throughput mapping of the phage resistance landscape inE. coli

Mutalik¹,

Adler²,

Rishi³

et al. 2020

Preprint

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Bacteriophages (phages) are critical players in the dynamics and function of microbial communities and drive processes as diverse as global biogeochemical cycles and human health. Phages tend to be predators finely tuned to attack specific hosts, even down to the strain level, which in turn defend themselves using an array of mechanisms. However, to date, efforts to rapidly and comprehensively identify bacterial host factors important in phage infection and resistance have yet to be fully realized. Here, we globally map the host genetic determinants involved in resistance to 14 phylogenetically diverse double-stranded DNA phages using two model Escherichia coli strains (K-12 and BL21) with known sequence divergence to demonstrate strain-specific differences. Using genome-wide loss-of-function and gain-of-function genetic technologies, we are able to confirm previously described phage receptors as well as uncover a number of previously unknown host factors that confer resistance to one or more of these phages. We uncover differences in resistance factors that strongly align with the susceptibility of K-12 and BL21 to specific phage. We also identify both phage specific mechanisms, such as the unexpected role of cyclic-di-GMP in host sensitivity to phage N4, and more generic defenses, such as the overproduction of colanic acid capsular polysaccharide that defends against a wide array of phages. Our results indicate that host responses to phages can occur via diverse cellular mechanisms. Our systematic and highthroughput genetic workflow to characterize phage-host interaction determinants can be extended to diverse bacteria to generate datasets that allow predictive models of how phagemediated selection will shape bacterial phenotype and evolution. The results of this study and future efforts to map the phage resistance landscape will lead to new insights into the coevolution of hosts and their phage, which can ultimately be used to design better phage therapeutic treatments and tools for precision microbiome engineering.3 Introduction:

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“…Interestingly all of these proteins either are or interact directly with receptor binding proteins that mediate host recognition, a fundamental step for successful viral infection [23,24]. The enhanced pN/pS observed for these genes at the DCM provides evidence that this habitat is a micro-diversity hot-spot for viral receptor binding proteins.…”

Section: The Dcm Is a Micro-diversity Hot-spot For Viral Receptor Binmentioning

confidence: 99%

Associations between depth and micro-diversity within marine viral communities revealed through metagenomics

Coutinho

Rosselli

Rodrı́guez-Valera

2019

Preprint

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Viruses are extremely abundant and diverse biological entities that contribute to the functioning of marine ecosystems. Despite their recognized importance no studies have addressed trends of micro-diversity in marine viral communities across depth gradients. To fill this gap we obtained metagenomes from both the cellular and viral fractions of Mediterranean seawater samples spanning the epipelagic to the bathypelagic zone at 15, 45, 60 and 2000 meters deep. The majority of viral genomic sequences obtained were derived from bacteriophages of the order Caudovirales,

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Targeting mechanisms of tailed bacteriophages

Cited by 369 publications

References 184 publications

K. pneumoniaeST258 genomic variability and bacteriophage susceptibility

K. pneumoniaeST258 genomic variability and bacteriophage susceptibility

High-throughput mapping of the phage resistance landscape inE. coli

Associations between depth and micro-diversity within marine viral communities revealed through metagenomics

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