Phage Therapy: A Renewed Approach to Combat Antibiotic-Resistant Bacteria

Kortright, Kaitlyn E.; Chan, Benjamin K; Koff, Jonathan L.; Turner, Paul

doi:10.1016/j.chom.2019.01.014

Cited by 851 publications

(666 citation statements)

References 90 publications

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“…Any changes in levels or structure of these receptors can compromise efficient phage infection, thereby leading to an improvement in host fitness in the presence of phages. Consequently, receptor mutants are the most commonly found candidates that display phage resistance [48,49,52,57,87,89]. To confirm the validity of our approach, we looked for receptors recognized by many of the canonical phages used in this study for which there is published data available [49,50,[90][91][92][93][94][95][96].…”

Section: Rb-tnseq Identifies Known Receptors and Host Factors For Allmentioning

confidence: 94%

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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Section: Rb-tnseq Identifies Known Receptors and Host Factors For Allmentioning

confidence: 94%

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

Mutalik¹,

Adler²,

Rishi³

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…control of antibiotic-resistant bacteria, stabilisation of healthy gut microbes) have been considered. 27,28 Therefore, the elucidation of the symbiotic effects of viruses on the physiological functions and immune responses of their hosts, as well as clarification of the functional mechanisms involved, will lead to an understanding of the essential roles of viruses in regulating the biological processes of their hosts.…”

Section: Beneficial Effects Of Viral Infection On Mammalian Hostsmentioning

confidence: 99%

Villains or heroes? The raison d'être of viruses

Watanabe

Kawaoka

2020

Clin & Trans Imm

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The relationship between humans and viruses has a long history. Since the first identification of viruses in the 19th century, we have considered them to be 'pathogens' and have studied their mechanisms of replication and pathogenicity to combat the diseases that they cause. However, the relationships between hosts and viruses are various and virus infections do not necessarily cause diseases in their hosts. Rather, recent studies have shown that viral infections sometimes have beneficial effects on the biological functions and/or evolution of hosts. Here, we provide some insight into the positive side of viruses.

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“…This finding further supports the importance of phage structure in the evolution of niche breadth, a result that may have implications for public health surveillance and in therapy. For example, insofar as variation in structural genes is associated with different niche breadth exploitation, perhaps these genes can be manipulated to facilitate a phage's ability to fight particular infections, as in phage therapy (Kortright, Chan, Koff, & Turner, 2019). In addition, if phage genes are associated with expansion of host range, then they may be candidates for a "watch list" approach in disease surveillance, where natural populations are surveyed for mutations associated with exploiting new hosts (Patel, Quates, Johnson, & Ytreberg, 2019).…”

Section: Con Clus Ionsmentioning

confidence: 99%

Experimental evolution for niche breadth in bacteriophage T4 highlights the importance of structural genes

Pham

Ogbunugafor

et al. 2019

MicrobiologyOpen

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Ecologists have long studied the evolution of niche breadth, including how variability in environments can drive the evolution of specialism and generalism. This concept is of particular interest in viruses, where niche breadth evolution may explain viral disease emergence, or underlie the potential for therapeutic measures like phage therapy. Despite the significance and potential applications of virus–host interactions, the genetic determinants of niche breadth evolution remain underexplored in many bacteriophages. In this study, we present the results of an evolution experiment with a model bacteriophage system, Escherichia virus T4, in several host environments: exposure to Escherichia coli C, exposure to E. coli K‐12, and exposure to both E. coli C and E. coli K‐12. This experimental framework allowed us to investigate the phenotypic and molecular manifestations of niche breadth evolution. First, we show that selection on different hosts led to measurable changes in phage productivity in all experimental populations. Second, whole—genome sequencing of experimental populations revealed signatures of selection. Finally, clear and consistent patterns emerged across the host environments, especially the presence of new mutations in phage structural genes—genes encoding proteins that provide morphological and biophysical integrity to a virus. A comparison of mutations found across functional gene categories revealed that structural genes acquired significantly more mutations than other categories. Our findings suggest that structural genes are central determinants in bacteriophage niche breadth.

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Phage Therapy: A Renewed Approach to Combat Antibiotic-Resistant Bacteria

Cited by 851 publications

References 90 publications

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

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

Villains or heroes? The raison d'être of viruses

Experimental evolution for niche breadth in bacteriophage T4 highlights the importance of structural genes

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