Systematic exploration of Escherichia coli phage–host interactions with the BASEL phage collection

PLoS Biology, Journal Year: 2021, Volume and Issue: 19(11), P. e3001424 - e3001424

Published: Nov. 16, 2021

Bacteriophages, the viruses infecting bacteria, hold great potential for treatment of multidrug-resistant bacterial infections and other applications due to their unparalleled diversity recent breakthroughs in genetic engineering. However, fundamental knowledge molecular mechanisms underlying phage–host interactions is mostly confined a few traditional model systems did not keep pace with massive expansion field. The true biology encoded by these has therefore remained largely untapped, phages therapy or are often still selected empirically. We sought promote systematic exploration composing well-assorted library 68 newly isolated organism Escherichia coli that we share community as BASEL (BActeriophage SElection your Laboratory) collection. This collection representative natural E . phage was intensively characterized phenotypically genomically alongside 10 well-studied phages. experimentally determined essential host receptors all phages, quantified sensitivity 11 defense across different layers immunity, matched results phages’ range panel pathogenic enterobacterial strains. Clear patterns distribution phenotypes genomic features highlighted differences potency immunity suggested basis receptor specificity several groups. Our also indicate strong trade-offs between fitness traits like broad recognition resistance might drive divergent adaptation groups specific ecological niches. envision will inspire future work exploring bacteriophages hosts facilitating discovery an effective translation into biotechnology therapeutic applications.

Language: Английский

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Programmable protein delivery with a bacterial contractile injection system

Nature, Journal Year: 2023, Volume and Issue: 616(7956), P. 357 - 364

Published: March 29, 2023

Abstract Endosymbiotic bacteria have evolved intricate delivery systems that enable these organisms to interface with host biology. One example, the extracellular contractile injection (eCISs), are syringe-like macromolecular complexes inject protein payloads into eukaryotic cells by driving a spike through cellular membrane. Recently, eCISs been found target mouse 1–3 , raising possibility could be harnessed for therapeutic delivery. However, whether can function in human remains unknown, and mechanism which recognize is poorly understood. Here we show selection Photorhabdus virulence cassette (PVC)—an eCIS from entomopathogenic bacterium asymbiotica —is mediated specific recognition of receptor distal binding element PVC tail fibre. Furthermore, using silico structure-guided engineering fibre, PVCs reprogrammed not natively targeted systems—including mice—with efficiencies approaching 100%. Finally, load diverse payloads, including Cas9, base editors toxins, functionally deliver them cells. Our results demonstrate programmable devices possible applications gene therapy, cancer therapy biocontrol.

Language: Английский

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Bacteriophage-based advanced bacterial detection: Concept, mechanisms, and applications

Biosensors and Bioelectronics, Journal Year: 2021, Volume and Issue: 177, P. 112973 - 112973

Published: Jan. 9, 2021

Language: Английский

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Coevolutionary phage training leads to greater bacterial suppression and delays the evolution of phage resistance

Proceedings of the National Academy of Sciences, Journal Year: 2021, Volume and Issue: 118(23)

Published: June 3, 2021

Significance The evolution of antibiotic-resistant bacteria threatens to claim over 10 million lives annually by 2050. This crisis has renewed interest in phage therapy, the use bacterial viruses treat infections. A major barrier successful therapy is that readily evolve resistance. One idea proposed combat resistance “training” phages using their natural capacity counter Here, we show training coevolving them with hosts for 1 mo repeatably enhances suppressing growth and delays emergence Enhanced suppression was caused several mechanisms, suggesting coevolutionary protocol produces a robust therapeutic employs complementary modes action.

Language: Английский

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Protein Cages: From Fundamentals to Advanced Applications

Chemical Reviews, Journal Year: 2022, Volume and Issue: 122(9), P. 9145 - 9197

Published: April 8, 2022

Proteins that self-assemble into polyhedral shell-like structures are useful molecular containers both in nature and the laboratory. Here we review efforts to repurpose diverse protein cages, including viral capsids, ferritins, bacterial microcompartments, designed capsules, as vaccines, drug delivery vehicles, targeted imaging agents, nanoreactors, templates for controlled materials synthesis, building blocks higher-order architectures, more. A deep understanding of principles underlying construction, function, evolution natural systems has been key tailoring selective cargo encapsulation interactions with biological synthetic through engineering directed evolution. The ability adapt design increasingly sophisticated capsid functions stands benefit fields catalysis, science, medicine.

Language: Английский

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Understanding Bacteriophage Tail Fiber Interaction with Host Surface Receptor: The Key “Blueprint” for Reprogramming Phage Host Range

International Journal of Molecular Sciences, Journal Year: 2022, Volume and Issue: 23(20), P. 12146 - 12146

Published: Oct. 12, 2022

Bacteriophages (phages), as natural antibacterial agents, are being rediscovered because of the growing threat multi- and pan-drug-resistant bacterial pathogens globally. However, with an estimated 1031 phages on planet, finding right phage to recognize a specific host is like looking for needle in trillion haystacks. The range primarily determined by tail fibers (or spikes), which initially mediate reversible recognition adsorption susceptible bacteria. Recent significant advances at single-molecule atomic levels have begun unravel structural organization underlying mechanisms phage–host interactions. Here, we discuss molecular models well-characterized T4 phage’s interaction surface receptors. Structure–function knowledge will pave way reprogramming bring future benefits through more-effective therapy medicine. Furthermore, design strategies fiber engineering briefly summarized, including machine-learning-assisted inspired increasingly enormous amount genetic information.

Language: Английский

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In situ targeted base editing of bacteria in the mouse gut

Nature, Journal Year: 2024, Volume and Issue: 632(8026), P. 877 - 884

Published: July 10, 2024

Abstract Microbiome research is now demonstrating a growing number of bacterial strains and genes that affect our health 1 . Although CRISPR-derived tools have shown great success in editing disease-driving human cells 2 , we currently lack the to achieve comparable for targets situ. Here engineer phage-derived particle deliver base editor modify Escherichia coli colonizing mouse gut. Editing β-lactamase gene model E. strain resulted median efficiency 93% target population with single dose. Edited bacteria were stably maintained gut at least 42 days following treatment. This was achieved using non-replicative DNA vector, preventing maintenance dissemination payload. We then leveraged this approach edit several therapeutic relevance Klebsiella pneumoniae vitro demonstrate situ involved production curli pathogenic strain. Our work demonstrates feasibility modifying directly gut, offering new avenue investigate function opening door design microbiome-targeted therapies.

Language: Английский

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A Comprehensive Review on Phage Therapy and Phage-Based Drug Development

Antibiotics, Journal Year: 2024, Volume and Issue: 13(9), P. 870 - 870

Published: Sept. 11, 2024

Phage therapy, the use of bacteriophages (phages) to treat bacterial infections, is regaining momentum as a promising weapon against rising threat multidrug-resistant (MDR) bacteria. This comprehensive review explores historical context, modern resurgence phage and phage-facilitated advancements in medical technological fields. It details mechanisms action applications phages treating MDR particularly those associated with biofilms intracellular pathogens. The further highlights innovative uses vaccine development, cancer gene delivery vectors. Despite its targeted efficient approach, therapy faces challenges related stability, immune response, regulatory approval. By examining these areas detail, this underscores immense potential remaining hurdles integrating phage-based therapies into practices.

Language: Английский

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High-throughput mapping of the phage resistance landscape in E. coli

PLoS Biology, Journal Year: 2020, Volume and Issue: 18(10), P. e3000877 - e3000877

Published: Oct. 13, 2020

Bacteriophages (phages) are critical players in the dynamics and function of microbial communities drive processes as diverse global biogeochemical cycles human health. Phages tend to be predators finely tuned attack specific hosts, even down strain level, which turn defend themselves using an array mechanisms. However, date, efforts rapidly comprehensively identify bacterial host factors important phage infection resistance have yet fully realized. Here, we globally map genetic determinants involved 14 phylogenetically double-stranded DNA phages two model Escherichia coli strains (K-12 BL21) with known sequence divergence demonstrate strain-specific differences. Using genome-wide loss-of-function gain-of-function technologies, able confirm previously described receptors well uncover a number unknown that confer one or more these phages. We differences strongly align susceptibility K-12 BL21 phage. also both phage-specific mechanisms, such unexpected role cyclic-di-GMP sensitivity N4, generic defenses, overproduction colanic acid capsular polysaccharide defends against wide Our results indicate responses can occur via cellular systematic high-throughput workflow characterize phage-host interaction extended bacteria generate datasets allow predictive models how phage-mediated selection will shape phenotype evolution. The this study future landscape lead new insights into coevolution hosts their phage, ultimately used design better therapeutic treatments tools for precision microbiome engineering.

Language: Английский

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Enhancing phage therapy through synthetic biology and genome engineering

Current Opinion in Biotechnology, Journal Year: 2020, Volume and Issue: 68, P. 151 - 159

Published: Dec. 11, 2020

The antimicrobial and therapeutic efficacy of bacteriophages is currently limited, mostly due to rapid emergence phage-resistance the inability most phage isolates bind infect a broad range clinical strains. Here, we discuss how therapy can be improved through recent advances in genetic engineering. First, outline receptor-binding proteins their relevant structural domains are engineered redirect specificity avoid resistance. Next, summarize phages reprogrammed as prokaryotic gene vectors that deliver 'payload' proteins, such sequence-specific nucleases, target defined cells within complex microbiomes. Finally, delineate big data- novel artificial intelligence-driven approaches may guide design synthetic future.

Language: Английский

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