Bacteria-eating viruses could provide a route to stability in cystic fibrosis

Svoboda, Elizabeth

doi:10.1038/d41586-020-02109-7

Cited by 10 publications

(6 citation statements)

References 3 publications

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“…Infections caused by the Gram-negative pathogen P. aeruginosa are a leading cause of morbidity and mortality worldwide. Phage therapy against P. aeruginosa has gained attention as a promising therapeutic weapon, especially in the ght against cystic brosis-related infections 45,46 . The N4-like phage DEV is part of an experimental phage cocktail to eradicate P. aeruginosa infections in vivo 8, 9 .…”

Section: Discussionmentioning

confidence: 99%

Integrative structural analysis of Pseudomonas phage DEV reveals a genome ejection motor

Cingolani,

Lokareddy,

Hou

et al. 2024

Preprint

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DEV is an obligatory lytic Pseudomonas phage of the N4-like genus, recently reclassified as Schitoviridae. The DEV genome encodes 91 ORFs, including a 3,398 amino acid virion-associated RNA polymerase. Here, we describe the complete architecture of DEV, determined using a combination of cryo-electron microscopy localized reconstruction, biochemical methods, and genetic knockouts. We built de novo structures of all capsid factors and tail components involved in host attachment. We demonstrate that DEV long tail fibers are essential for infection of Pseudomonas aeruginosa and dispensable for infecting mutants with a truncated lipopolysaccharide devoid of the O-antigen. We identified DEV ejection proteins and, unexpectedly, found that the giant DEV RNA polymerase, the hallmark of the Schitoviridae family, is an ejection protein. We propose that DEV ejection proteins form a genome ejection motor across the host cell envelope and that these structural principles are conserved in all Schitoviridae.

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Section: Discussionmentioning

confidence: 99%

Integrative structural analysis of Pseudomonas phage DEV reveals a genome ejection motor

Cingolani,

Lokareddy,

Hou

et al. 2024

Preprint

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“…Phage treatments generally are thought to be more effective against newer, acute bacterial infections, e.g., when phage treatments are initiated days rather than months after the start of infections or indeed prophylactically [22], and this preference presumably stems from target bacteria not having yet entered into more phage-resistant physical or physiological states (e.g., [23]). In practice, however, published clinical treatments are typically of chronic or persistent bacterial infections [24], and particularly infections which antibiotic treatments have failed to cure [25][26][27][28]. Published clinical phage therapy also has primarily been undertaken under the auspices of compassionate use or treatment (a.k.a.…”

Section: Complicating Factorsmentioning

confidence: 99%

Phage Therapy in the 21st Century: Is There Modern, Clinical Evidence of Phage-Mediated Efficacy?

2021

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Many bacteriophages are obligate killers of bacteria. That this property could be medically useful was first recognized over one hundred years ago, with 2021 being the 100-year anniversary of the first clinical phage therapy publication. Here we consider modern use of phages in clinical settings. Our aim is to answer one question: do phages serve as effective anti-bacterial infection agents when used clinically? An important emphasis of our analyses is on whether phage therapy-associated anti-bacterial infection efficacy can be reasonably distinguished from that associated with often coadministered antibiotics. We find that about half of 70 human phage treatment reports—published in English thus far in the 2000s—are suggestive of phage-mediated anti-bacterial infection efficacy. Two of these are randomized, double-blinded, infection-treatment studies while 14 of those studies, in our opinion, provide superior evidence of a phage role in observed treatment successes. Roughly three-quarters of these potentially phage-mediated outcomes are based on microbiological as well as clinical results, with the rest based on clinical success. Since many of these phage treatments are of infections for which antibiotic therapy had not been successful, their collective effectiveness is suggestive of a valid utility in employing phages to treat otherwise difficult-to-cure bacterial infections.

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“…Bacteriophages, or phages-the viruses of bacteria-can be used as antibacterial agents against numerous types of bacterial infections. In this modern era, this is especially directed toward treating chronic bacterial infections against which antibiotic treatments either have been unsuccessful or are otherwise not possible [2][3][4][5][6]. Such phage therapy can involve application of only a single phage type (monophage).…”

Section: Introductionmentioning

confidence: 99%

Phage Cocktail Development for Bacteriophage Therapy: Toward Improving Spectrum of Activity Breadth and Depth

2021

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Phage therapy is the use of bacterial viruses as antibacterial agents. A primary consideration for commercial development of phages for phage therapy is the number of different bacterial strains that are successfully targeted, as this defines the breadth of a phage cocktail’s spectrum of activity. Alternatively, phage cocktails may be used to reduce the potential for bacteria to evolve phage resistance. This, as we consider here, is in part a function of a cocktail’s ‘depth’ of activity. Improved cocktail depth is achieved through inclusion of at least two phages able to infect a single bacterial strain, especially two phages against which bacterial mutation to cross resistance is relatively rare. Here, we consider the breadth of activity of phage cocktails while taking both depth of activity and bacterial mutation to cross resistance into account. This is done by building on familiar algorithms normally used for determination solely of phage cocktail breadth of activity. We show in particular how phage cocktails for phage therapy may be rationally designed toward enhancing the number of bacteria impacted while also reducing the potential for a subset of those bacteria to evolve phage resistance, all as based on previously determined phage properties.

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Bacteria-eating viruses could provide a route to stability in cystic fibrosis

Abstract: Bacteria-eating viruses are broadening the treatment landscape for people with drug-resistant infections. By Elizabeth Svoboda Ella Balasa inhales a phage treatment at Winchester Chest Clinic in New Haven, Connecticut.

Cited by 10 publications

References 3 publications

Integrative structural analysis of Pseudomonas phage DEV reveals a genome ejection motor

Integrative structural analysis of Pseudomonas phage DEV reveals a genome ejection motor

Phage Therapy in the 21st Century: Is There Modern, Clinical Evidence of Phage-Mediated Efficacy?

Phage Cocktail Development for Bacteriophage Therapy: Toward Improving Spectrum of Activity Breadth and Depth

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