Phage therapy: From biological mechanisms to future directions

Cell, Journal Year: 2023, Volume and Issue: 186(1), P. 17 - 31

Published: Jan. 1, 2023

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 bacterial host efficiently, and (3) fully characterized exclude side effects. Developing therapeutic takes a coordinated effort multiple stakeholders. Herein, we review state art in phage therapy, covering biological mechanisms, clinical applications, remaining challenges, future directions involving naturally occurring genetically modified or synthetic phages.

Language: Английский

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Microbiome and cancer

Cancer Cell, Journal Year: 2021, Volume and Issue: 39(10), P. 1317 - 1341

Published: Sept. 9, 2021

Language: Английский

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Considerations for the Use of Phage Therapy in Clinical Practice

Antimicrobial Agents and Chemotherapy, Journal Year: 2022, Volume and Issue: 66(3)

Published: Jan. 18, 2022

Increasing antimicrobial resistance and medical device-related infections have led to a renewed interest in phage therapy as an alternative or adjunct conventional antimicrobials. Expanded access compassionate use cases risen exponentially but varied widely approach, methodology, clinical situations which might be considered, dosing, route of administration, outcomes.

Language: Английский

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Phage Therapy in the Resistance Era: Where Do We Stand and Where Are We Going?

Clinical Therapeutics, Journal Year: 2020, Volume and Issue: 42(9), P. 1659 - 1680

Published: Aug. 31, 2020

PurposeWidespread antibiotic-resistant bacteria are threatening the arsenal of existing antibiotics. Not only antibiotics less likely to be effective today, but their extensive use continues drive emergence multidrug-resistant pathogens. A new-old antibacterial strategy with bacteriophages (phages) is under development, namely, phage therapy. Phages targeted bacterial viruses multiple effector functions, which can reduce infections within human body. This review summarizes recent therapy clinical trials and patient cases outlines fundamentals behind treatment strategies mainly through bench-to-bedside approaches. We discuss challenges that remain in role phages when combined antibiotic therapy.MethodsThis narrative presents current knowledge latest findings regarding Relevant case reports research articles available Scopus PubMed databases discussed.FindingsAlthough data suggest tolerability and, some cases, efficacy therapy, functionality still requires careful definition. The lack well-controlled trial complex regulatory frameworks have driven most generation on a single-patient compassionate basis. These often include concomitant antibiotics, makes it difficult draw conclusions effectiveness alone. However, support using as potentiators resistance breakers; thus, adjuvants promising avenue for near-term development. Current gaps exist appropriate routes administration, selection, frequency dosage, resistance, pharmacokinetic pharmacodynamic properties phages. In addition, we highlight therapies mild adverse effects patients.ImplicationsAlthough more translational needed before implementation feasible, may well pivotal safeguarding humans against infections.

Language: Английский

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The Safety and Toxicity of Phage Therapy: A Review of Animal and Clinical Studies

Viruses, Journal Year: 2021, Volume and Issue: 13(7), P. 1268 - 1268

Published: June 29, 2021

Increasing rates of infection by antibiotic resistant bacteria have led to a resurgence interest in bacteriophage (phage) therapy. Several phage therapy studies animals and humans been completed over the last two decades. We conducted systematic review safety toxicity data associated with both reported English language publications from 2008–2021. Overall, 69 met our eligibility criteria including 20 animal studies, 35 clinical case reports or series, 14 trials. After summarizing these publications, we discuss potential approaches optimize monitoring therapeutic use moving forward. In literature, found some adverse events therapy, but serious were extremely rare. Comprehensive standardized reporting toxicities has generally lacking published literature. Structured tolerability endpoints are necessary when phages administered as anti-infective therapeutics.

Language: Английский

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

Pharmaceuticals, Journal Year: 2021, Volume and Issue: 14(10), P. 1019 - 1019

Published: Oct. 3, 2021

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

Language: Английский

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Bacteriophage uptake by mammalian cell layers represents a potential sink that may impact phage therapy

iScience, Journal Year: 2021, Volume and Issue: 24(4), P. 102287 - 102287

Published: March 9, 2021

It is increasingly apparent that bacteriophages, viruses infect bacteria and more commonly referred to as simply phages, have tropisms outside their bacterial hosts. Using live tissue culture cell imaging, we demonstrate type, phage size, morphology play a major role in internalization. Uptake was validated under physiological conditions using microfluidic device. Phages adhered mammalian tissues, with adherent phages being subsequently internalized by macropinocytosis, functional accumulating intracellularly. We incorporated these results into pharmacokinetic model demonstrating the potential impact of accumulation layers, which represents sink for circulating body. During therapy, high doses are directly administered patient order treat infection, thereby facilitating broad interactions between cells. Understanding will important implications on innate immune responses, pharmacokinetics, efficacy therapy.

Language: Английский

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Engineered Bacteriophage Therapeutics: Rationale, Challenges and Future

BioDrugs, Journal Year: 2021, Volume and Issue: 35(3), P. 255 - 280

Published: April 21, 2021

The current problems with increasing bacterial resistance to antibacterial therapies, resulting in a growing frequency of incurable infections, necessitates the acceleration studies on antibacterials new generation that could offer an alternative antibiotics or support their action. Bacteriophages (phages) can kill antibiotic-sensitive as well antibiotic-resistant bacteria, and thus are major subject such studies. Their efficacy curing infections has been demonstrated vivo experiments clinic. Unlike antibiotics, phages have narrow range specificity, which makes them safe for commensal microbiota. However, targeting even only most clinically relevant strains pathogenic bacteria requires large collections characterized phages, whose specificity would cover all strains. environment is rich source diverse but due complex relationships safety concerns, some naturally occurring be considered therapeutic applications. Still, number diversity make detailed characterization potentially promising virtually impossible. Moreover, no single phage combines features required ideal agent. Additionally, rapid acquisition by may already approved therapy ineffective turn search environmental better into endless race. An strategy acquiring desired properties short time minimal cost regarding acquisition, characterization, approval based targeted genome modifications isolates known properties. first example demonstrating potential this diseases resistant traditional recent successful treatment progressing disseminated Mycobacterium abscessus infection teenage patient use engineered phage. In review, we briefly present methods genetic engineering, highlighting advantages disadvantages, provide examples genetically modified host range, improved activity, proven efficacy. We also summarize novel uses not killing situ modification human microbiota attenuate symptoms certain metabolic, immune, mental disorders.

Language: Английский

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PhageLeads: Rapid Assessment of Phage Therapeutic Suitability Using an Ensemble Machine Learning Approach

Viruses, Journal Year: 2022, Volume and Issue: 14(2), P. 342 - 342

Published: Feb. 8, 2022

The characterization of therapeutic phage genomes plays a crucial role in the success rate therapies. There are three checkpoints that need to be examined for selection candidates, namely, presence temperate markers, antimicrobial resistance (AMR) genes, and virulence genes. However, currently, no single-step tools available this purpose. Hence, we have developed tool capable checking all conditions required suitable candidates. This consists an ensemble machine-learning-based predictors determining markers (integrase, Cro/CI repressor, immunity DNA partitioning protein A, antirepressor) along with integration ABRicate determine antibiotic genes Using biological features were able predict high MCC scores (>0.70), corresponding lifestyle phages accuracy 96.5%. Additionally, screening 183 lytic revealed six found contain AMR or showing not used therapy. suite predictors, PhageLeads, integrated tool, can accessed online silico candidates from single genome metagenomic contigs.

Language: Английский

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Translating phage therapy into the clinic: Recent accomplishments but continuing challenges

PLoS Biology, Journal Year: 2023, Volume and Issue: 21(5), P. e3002119 - e3002119

Published: May 23, 2023

Phage therapy is a medical form of biological control bacterial infections, one that uses naturally occurring viruses, called bacteriophages or phages, as antibacterial agents. Pioneered over 100 years ago, phage nonetheless currently experiencing resurgence in interest, with growing numbers clinical case studies being published. This renewed enthusiasm due large part to holding promise for providing safe and effective cures infections traditional antibiotics acting alone have been unable clear. Essay introduces basic biology, provides an outline the long history therapy, highlights some advantages using phages agents, overview recent successes. Although has clear potential, it faces biological, regulatory, economic challenges its further implementation more mainstream acceptance.

Language: Английский

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