Alternative treatment modes for antibiotic-resistant bacterial pathogens have become a public health priority. Bacteriophages are bacterial viruses that infect and lyse bacterial cells. Since ...bacteriophages are frequently bacterial host species-specific and can often also infect antibiotic-resistant bacterial cells, they could represent ideal antimicrobials for fighting the antibiotic resistance crisis. The medical use of bacteriophages has become known as phage therapy. It is widely used in Russia, where phage cocktails are sold in pharmacies as an over-the-counter drug. However, no phage product has been registered for medical purposes outside of the former Soviet Union. The current Special Issue of Viruses contains a collection of papers from opinion leaders in the field who explore hurdles to the introduction of phage therapy in western countries. The articles cover diverse topics ranging from patent to regulatory issues, the targeting of suitable bacterial infections, and the selection and characterization of safe and efficient phage cocktails. Phage resistance is discussed, and gaps in our knowledge of phage–bacterium interactions in the mammalian body are revealed, while other articles explore the use of phages in food production and processing.
Done a lot of cases successfully in our place with bacteriophages in small nonhealing chronic wounds but its use in extensive infected burn wound healing is also encouraging. Our clinical evidence of ...topical application of bacteriophages on extensive multi-drug resistant MDR bacterial infected burn wounds has been done for the first time and has never been reported in the literature. The medical revolution is on the horizon for treating superbugs and their positive effect on the economy especially in treating skin wounds.
CrAssphages represent the most abundant virus in the human gut microbiota, but the lack of available genome sequences for comparison has kept them enigmatic. Recently, sequence-based classification ...of distantly related crAss-like phages from multiple environments was reported, leading to a proposed familial-level taxonomic group. Here, we assembled the metagenomic sequencing reads from 702 human fecal virome/phageome samples and analyzed 99 complete circular crAss-like phage genomes and 150 contigs ≥70 kb. In silico comparative genomics and taxonomic analysis enabled a classification scheme of crAss-like phages from human fecal microbiomes into four candidate subfamilies composed of ten candidate genera. Laboratory analysis was performed on fecal samples from an individual harboring seven distinct crAss-like phages. We achieved crAss-like phage propagation in ex vivo human fecal fermentations and visualized short-tailed podoviruses by electron microscopy. Mass spectrometry of a crAss-like phage capsid protein could be linked to metagenomic sequencing data, confirming crAss-like phage structural annotations.
Display omitted
•Screening of human fecal metagenomic samples reveals 249 crAss-like phage genomes•The crAss-like phages were classified into 4 subfamilies composed of 10 candidate genera•A crAss-like phage was propagated in ex vivo human fecal fermentations•Short-tailed phage virions could be visualized by electron microscopy
CrAssphage is the most abundant human gut-associated virus. Guerin et al. identify 249 crAss-like phage genomes and classify them into four subfamilies and ten candidate genera that differ among human populations. These in silico predictions are combined with ex vivo propagations, electron microscopy imaging, and mass spectrometry detection.
Statistical structure of host—phage interactions Flores, Cesar O.; Meyer, Justin R.; Valverde, Sergi ...
Proceedings of the National Academy of Sciences,
07/2011, Volume:
108, Issue:
28
Journal Article
Peer reviewed
Open access
Interactions between bacteria and the viruses that infect them (i.e., phages) have profound effects on biological processes, but despite their importance, little is known on the general structure of ...infection and resistance between most phages and bacteria. For example, are bacteria–phage communities characterized by complex patterns of overlapping exploitation networks, do they conform to a more ordered general pattern across all communities, or are they idiosyncratic and hard to predict from one ecosystem to the next? To answer these questions, we collect and present a detailed metaanalysis of 38 laboratory-verified studies of host–phage interactions representing almost 12,000 distinct experimental infection assays across a broad spectrum of taxa, habitat, and mode of selection. In so doing, we present evidence that currently available host–phage infection networks are statistically different from random networks and that they possess a characteristic nested structure. This nested structure is typified by the finding that hard to infect bacteria are infected by generalist phages (and not specialist phages) and that easy to infect bacteria are infected by generalist and specialist phages. Moreover, we find that currently available host–phage infection networks do not typically possess a modular structure. We explore possible underlying mechanisms and significance of the observed nested host–phage interaction structure. In addition, given that most of the available host–phage infection networks examined here are composed of taxa separated by short phylogenetic distances, we propose that the lack of modularity is a scale-dependent effect, and then, we describe experimental studies to test whether modular patterns exist at macroevolutionary scales.
Bacteriophages typically have small genomes
and depend on their bacterial hosts for replication
. Here we sequenced DNA from diverse ecosystems and found hundreds of phage genomes with lengths of ...more than 200 kilobases (kb), including a genome of 735 kb, which is-to our knowledge-the largest phage genome to be described to date. Thirty-five genomes were manually curated to completion (circular and no gaps). Expanded genetic repertoires include diverse and previously undescribed CRISPR-Cas systems, transfer RNAs (tRNAs), tRNA synthetases, tRNA-modification enzymes, translation-initiation and elongation factors, and ribosomal proteins. The CRISPR-Cas systems of phages have the capacity to silence host transcription factors and translational genes, potentially as part of a larger interaction network that intercepts translation to redirect biosynthesis to phage-encoded functions. In addition, some phages may repurpose bacterial CRISPR-Cas systems to eliminate competing phages. We phylogenetically define the major clades of huge phages from human and other animal microbiomes, as well as from oceans, lakes, sediments, soils and the built environment. We conclude that the large gene inventories of huge phages reflect a conserved biological strategy, and that the phages are distributed across a broad bacterial host range and across Earth's ecosystems.
Bacteriophages can influence the abundance, diversity, and evolution of bacterial communities. Several bacteriophages have been reported to add virulence factors to their host and to increase ...bacterial virulence. However, lytic bacteriophages can also exert a selective pressure allowing the proliferation of strains with reduced virulence. This reduction can be explained because bacteriophages use structures present on the bacterial surface as receptors, which can be virulence factors in different bacterial species. Therefore, strains with modifications in these receptors will be resistant to bacteriophage infection and may also exhibit reduced virulence. This mini-review summarizes the reports on bacteriophage-resistant strains with reductions in virulence, and it discusses the potential consequences in phage therapy and in the use of bacteriophages to select attenuated strains for vaccines.
The global bacteriophage population is large, dynamic, old, and highly diverse genetically. Many phages are tailed and contain double-stranded DNA, but these remain poorly characterized genomically. ...A collection of over 1,000 phages infecting
reveals the diversity of phages of a common bacterial host, but their relationships to phages of phylogenetically proximal hosts are not known. Comparative sequence analysis of 79 phages isolated on
shows these also to be diverse and that the phages can be grouped into 14 clusters of related genomes, with an additional 14 phages that are "singletons" with no closely related genomes. One group of six phages is closely related to Cluster A mycobacteriophages, but the other
phages are distant relatives and share only 10% of their genes with the mycobacteriophages. The
phage genomes vary in genome length (17.1 to 103.4 kb), percentage of GC content (47 to 68.8%), and genome architecture and contain a variety of features not seen in other phage genomes. Like the mycobacteriophages, the highly mosaic
phages demonstrate a spectrum of genetic relationships. We show this is a general property of bacteriophages and suggest that any barriers to genetic exchange are soft and readily violable.
Despite the numerical dominance of bacteriophages in the biosphere, there is a dearth of complete genomic sequences. Current genomic information reveals that phages are highly diverse genomically and have mosaic architectures formed by extensive horizontal genetic exchange. Comparative analysis of 79 phages of
shows them to not only be highly diverse, but to present a spectrum of relatedness. Most are distantly related to phages of the phylogenetically proximal host
, although one group of
phages is more closely related to mycobacteriophages than to the other
phages. Phage genome sequence space remains largely unexplored, but further isolation and genomic comparison of phages targeted at related groups of hosts promise to reveal pathways of bacteriophage evolution.
The world is on the cusp of a post-antibiotic era, but researchers and medical doctors have found a way forward-by looking back at how infections were treated before the advent of antibiotics, namely ...using phage therapy. Although bacteriophages (phages) continue to lack drug approval in Western medicine, an increasing number of patients are being treated on an expanded-access emergency investigational new drug basis. To streamline the production of high-quality and clinically safe phage preparations, we developed a systematic procedure for medicinal phage isolation, liter-scale cultivation, concentration and purification. The 16- to 21-day procedure described in this protocol uses a combination of modified classic techniques, modern membrane filtration processes and no organic solvents to yield on average 23 mL of 10
plaque-forming units (PFUs) per milliliter for Pseudomonas, Klebsiella, and Serratia phages tested. Thus, a single production run can produce up to 64,000 treatment doses at 10
PFUs, which would be sufficient for most expanded-access phage therapy cases and potentially for clinical phase I/II applications. The protocol focuses on removing endotoxins early by conducting multiple low-speed centrifugations, microfiltration, and cross-flow ultrafiltration, which reduced endotoxins by up to 10
-fold in phage preparations. Implementation of a standardized phage cultivation and purification across research laboratories participating in phage production for expanded-access phage therapy might be pivotal to reintroduce phage therapy to Western medicine.
Increasing antimicrobial resistance rates have revitalized bacteriophage (phage) research, the natural predators of bacteria discovered over 100 years ago. In order to use phages therapeutically, ...they should (1) preferably be lytic, (2) kill the bacterial host efficiently, and (3) be fully characterized to exclude side effects. Developing therapeutic phages takes a coordinated effort of multiple stakeholders. Herein, we review the state of the art in phage therapy, covering biological mechanisms, clinical applications, remaining challenges, and future directions involving naturally occurring and genetically modified or synthetic phages.
Phage therapy has undergone a revitalization in the last 7 years, and a growing number of clinical trials are underway. This review provides a comprehensive view on the state of the art in phage therapy, covering biological mechanisms, clinical applications, remaining challenges, and future directions.
PDF
