Current challenges and future opportunities of phage therapy

Pires, Diana Priscila Penso; Costa, Ana Rita; Pinto, Graça; Meneses, Luciana; Azeredo, Joana

doi:10.1093/femsre/fuaa017

Cited by 211 publications

(153 citation statements)

References 191 publications

(210 reference statements)

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“…However, the molecular mechanisms and genetic basis underlying other desired features such as resistance to different bacterial immunity systems and, in general, the distribution of all these features across different groups of phages have remained understudied. Given the notable incidence of treatment failure in phage therapy [18][19][20], a better understanding of the links between phage taxonomy, genome sequence, and phenotypic properties seems timely to select more effective native phages for therapeutic applications and to expand the potential of phage engineering.…”

Section: Fig 1 the Three Morphotypes Of Caudovirales And Two Lines Omentioning

confidence: 99%

Systematic exploration ofEscherichia coliphage-host interactions with the BASEL phage collection

Maffei

Shaidullina

Burkolter

et al. 2021

Preprint

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Bacteriophages, the viruses infecting bacteria, hold great potential for the treatment of multidrug-resistant bacterial infections and other applications due to their unparalleled diversity and recent breakthroughs in their genetic engineering. However, fundamental knowledge of molecular mechanisms underlying phage-host interactions is mostly confined to a few traditional model systems and did not keep pace with the recent massive expansion of the field. The true potential of molecular biology encoded by these viruses has therefore remained largely untapped, and phages for therapy or other applications are often still selected empirically. We therefore sought to promote a systematic exploration of phage-host interactions by composing a well-assorted library of 66 newly isolated phages infecting the model organism Escherichia coli that we share with the community as the BASEL collection (BActeriophage SElection for your Laboratory). This collection is largely representative of natural E. coli phage diversity and was intensively characterized phenotypically and genomically alongside ten well-studied traditional model phages. We experimentally determined essential host receptors of all phages, quantified their sensitivity to eleven defense systems across different layers of bacterial immunity, and matched these results to the phages' host range across a panel of pathogenic enterobacterial strains. Our results reveal clear patterns in the distribution of phage phenotypes and genomic features that highlight systematic differences in the potency of different immunity systems and point towards the molecular basis of receptor specificity in several phage groups. Strong trade-offs were detected between fitness traits like broad host recognition and resistance to bacterial immunity that might drive the divergent adaptation of different phage groups to specific niches. We envision that the BASEL collection will inspire future work exploring the biology of bacteriophages and their hosts by facilitating the discovery of underlying molecular mechanisms as the basis for an effective translation into biotechnology or therapeutic applications.

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Section: Fig 1 the Three Morphotypes Of Caudovirales And Two Lines Omentioning

confidence: 99%

Systematic exploration ofEscherichia coliphage-host interactions with the BASEL phage collection

Maffei

Shaidullina

Burkolter

et al. 2021

Preprint

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“…Phage therapy has re-emerged because of its potential treatment for antimicrobial-resistant infections, and a common protocol for treatments is to select two or more phages for combination into a treatment cocktail (4)(5)(6). An ongoing issue is the establishment of criteria used for selection of appropriate phages for a cocktail, to enhance production and maximize efficacy, and to circumvent issues of phage-resistance and collateral induction of further drugresistance in the infection sites (4,6). The phages used for phage therapy are Caudovirales conforming to a blue-print of an icosahedral protein capsid housing the phage genome, and a tail composed of 20-40 protein components (10).…”

Section: Introductionmentioning

confidence: 99%

“…Bacteriophages (phages) that kill bacterial pathogens such as Klebsiella are being identified for use in phage therapies, with the intention to apply these bactericidal viruses directly into the infection sites. Careful consideration is needed in selecting the phages for use in therapeutic cocktails (4–6), considerations made difficult because annotation of phage genomes is poor (7, 8), potentially obscuring phages with therapeutic potential. For example, while structural motifs are now known (9) that will promote phage virion stability (i.e.…”

Section: Introductionmentioning

confidence: 99%

The component parts of bacteriophage virions accurately defined by a machine-learning approach built on evolutionary features

Thung

White

Dai

et al. 2021

Preprint

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Antimicrobial resistance (AMR) continues to evolve as a major threat to human health and new strategies are required for the treatment of AMR infections. Bacteriophages (phages) that kill bacterial pathogens are being identified for use in phage therapies, with the intention to apply these bactericidal viruses directly into the infection sites in bespoke phage cocktails. Despite the great unsampled phage diversity for this purpose, an issue hampering the roll out of phage therapy is the poor quality annotation of many of the phage genomes, particularly for those from infrequently sampled environmental sources. We developed a computational tool called STEP3 to use the “evolutionary features” that can be recognized in genome sequences of diverse phages. These features, when integrated into an ensemble framework, achieved a stable and robust prediction performance when benchmarked against other prediction tools using phages from diverse sources. Validation of the prediction accuracy of STEP3 was conducted with high-resolution mass spectrometry analysis of two novel phages, isolated from a watercourse in the Southern Hemisphere. STEP3 provides a robust computational approach to distinguish specific and universal features in phages to improve the quality of phage cocktails, and is available for use at http://step3.erc.monash.edu/.IMPORTANCEIn response to the global problem of antimicrobial resistance there are moves to use bacteriophages (phages) as therapeutic agents. Selecting which phages will be effective therapeutics relies on interpreting features contributing to shelf-life and applicability to diagnosed infections. However, the protein components of the phage virions that dictate these properties vary so much in sequence that best estimates suggest failure to recognize up to 90% of them. We have utilised this diversity in evolutionary features as an advantage, to apply machine learning for prediction accuracy for diverse components in phage virions. We benchmark this new tool showing the accurate recognition and evaluation of phage components parts using genome sequence data of phages from under-sampled environments, where the richest diversity of phage still lies.

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“…Under the circumstance of antibiotic drug resistance, phage therapy was found more and more important in the antibacterial theory either using alone or in combination with antibiotics [17][18][19]. Phage is exclusively virulent to prokaryotic microbe and do not lyse animal and human cells.…”

Section: Introductionmentioning

confidence: 99%

Biological Characteristics and Genomic Analysis of Aeromonas Hydrophila Phage BUCT551 Isolated From Aquatic Sewage

Qin

et al. 2021

Preprint

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Aeromonas hydrophila is a common opportunistic pathogen in aquaculture and is ubiquitous in aquatic environment. Whereby its accessibility, variety and host specificity, phage is increasingly considered as a promising complementary medicine for antibiotics. However, a small amount of A. hydrophila phages have been characterized, which suggests the significance to isolate and characterize novel A. hydrophila phages. In this study, we isolated a novel Aeromonas hydrophila phage using A. hydrophila strain A18 as an indicator and designated it as BUCT551, and it was identified as Myoviridae phage by transmission electron microscopy (TEM). The whole genome sequencing of the phage BUCT551 revealed that it has a linear DNA genome of 613,82 bp. BLASTn analysis showed that phage BUCT551 shared 86.75% homology with A. hydrophila phage LAh_7 (Genebank ID: MK838113.1). The one-step growth curve demonstrated that phage BUCT551 had a latent period of 20 min and the burst size of 32 pfu/cell at its optimal MOI of 0.1. The phage BUCT551 had a survival pH range from 5 to 10 and tolerant temperature from 0℃ to 40℃. Host range analysis shown that the phage was able to lyse not only A. hydrophila, but also A. veronii.

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Current challenges and future opportunities of phage therapy

Cited by 211 publications

References 191 publications

Systematic exploration ofEscherichia coliphage-host interactions with the BASEL phage collection

Systematic exploration ofEscherichia coliphage-host interactions with the BASEL phage collection

The component parts of bacteriophage virions accurately defined by a machine-learning approach built on evolutionary features

Biological Characteristics and Genomic Analysis of Aeromonas Hydrophila Phage BUCT551 Isolated From Aquatic Sewage

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