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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Direct activation of a bacterial innate immune system by a viral capsid protein

Nature, Journal Year: 2022, Volume and Issue: 612(7938), P. 132 - 140

Published: Nov. 16, 2022

Abstract Bacteria have evolved diverse immunity mechanisms to protect themselves against the constant onslaught of bacteriophages 1–3 . Similar how eukaryotic innate immune systems sense foreign invaders through pathogen-associated molecular patterns 4 (PAMPs), many bacterial that respond bacteriophage infection require phage-specific triggers be activated. However, identities such and sensing remain largely unknown. Here we identify investigate anti-phage function CapRel SJ46 , a fused toxin–antitoxin system protects Escherichia coli phages. Using genetic, biochemical structural analyses, demonstrate C-terminal domain regulates toxic N-terminal region, serving as both antitoxin phage sensor. Following by certain phages, newly synthesized major capsid protein binds directly relieve autoinhibition, enabling toxin pyrophosphorylate tRNAs, which blocks translation restrict viral infection. Collectively, our results reveal mechanism senses conserved, essential component suggesting PAMP-like model for toxin–antitoxin-mediated in bacteria. We provide evidence CapRels their phage-encoded are engaged ‘Red Queen conflict’ 5 revealing new front intense coevolutionary battle between phages Given proteins some viruses known stimulate signalling mammalian hosts 6–10 deeply conserved facet immunity.

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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Resolving the structure of phage–bacteria interactions in the context of natural diversity

Nature Communications, Journal Year: 2022, Volume and Issue: 13(1)

Published: Jan. 18, 2022

Microbial communities are shaped by viral predators. Yet, resolving which viruses (phages) and bacteria interacting is a major challenge in the context of natural levels microbial diversity. Thus, fundamental features how phage-bacteria interactions structured evolve wild remain poorly resolved. Here we use large-scale isolation environmental marine Vibrio their phages to obtain estimates strain-level phage predator loads, all-by-all host range assays discover genomic diversity shape interactions. We show that lytic interaction networks (as observed agar overlay) sparse-with loads being low for most bacterial strains, host-strain-specific. Paradoxically, also find although overlap killing generally rare between tailed phages, recombination common. Together, these results suggest during cryptic co-infections an important mode evolution communities. In development bioengineering therapeutics it consider nucleic acids introduced may spread into local populations through recombination, likelihood transfer not predictable based on range.

Language: Английский

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Antibiotic polymyxin arranges lipopolysaccharide into crystalline structures to solidify the bacterial membrane

Nature Communications, Journal Year: 2022, Volume and Issue: 13(1)

Published: Oct. 21, 2022

Polymyxins are last-resort antibiotics with potent activity against multi-drug resistant pathogens. They interact lipopolysaccharide (LPS) in bacterial membranes, but mechanistic details at the molecular level remain unclear. Here, we characterize interaction of polymyxins native, LPS-containing outer membrane patches Escherichia coli by high-resolution atomic force microscopy imaging, along structural and biochemical assays. We find that arrange LPS into hexagonal assemblies to form crystalline structures. Formation structures is correlated antibiotic activity, absent polymyxin-resistant strains. Crystal lattice parameters alter variations polymyxin molecules. Quantitative measurements show decrease thickness increase area as well stiffness. Together, these findings suggest formation rigid LPS-polymyxin crystals subsequent disruption mechanism action provide a benchmark for optimization de novo design LPS-targeting antimicrobials.

Language: Английский

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A swapped genetic code prevents viral infections and gene transfer

Nature, Journal Year: 2023, Volume and Issue: 615(7953), P. 720 - 727

Published: March 15, 2023

Language: Английский

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Genetic determinants of host tropism in Klebsiella phages

Cell Reports, Journal Year: 2023, Volume and Issue: 42(2), P. 112048 - 112048

Published: Feb. 1, 2023

Bacteriophages play key roles in bacterial ecology and evolution are potential antimicrobials. However, the determinants of phage-host specificity remain elusive. Here, we isolate 46 phages to challenge 138 representative clinical isolates Klebsiella pneumoniae, a widespread opportunistic pathogen. Spot tests show narrow host range for most phages, with <2% 6,319 combinations tested yielding detectable interactions. Bacterial capsule diversity is main factor restricting phage range. Consequently, phage-encoded depolymerases tropism, depolymerase sequence types associated ability infect specific capsular across families. all broader found do not encode canonical depolymerases, suggesting alternative modes entry. These findings expand our knowledge complex interactions between bacteria their viruses point out feasibility predicting first steps infection using genome sequences.

Language: Английский

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Phage Paride can kill dormant, antibiotic-tolerant cells of Pseudomonas aeruginosa by direct lytic replication

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: Jan. 2, 2024

Abstract Bacteriophages are ubiquitous viral predators that have primarily been studied using fast-growing laboratory cultures of their bacterial hosts. However, microbial life in nature is mostly a slow- or non-growing, dormant state. Here, we show diverse phages can infect deep-dormant bacteria and suspend replication until the host resuscitates (“hibernation”). newly isolated Pseudomonas aeruginosa phage, named Paride, directly replicate induce lysis While non-growing notoriously tolerant to antibiotic drugs, combination with Paride enables carbapenem meropenem eradicate vitro reduce resilient infection tissue cage implant mice. Our work might inspire new treatments for persistent infections and, more broadly, highlights two strategies (hibernation direct replication) will guide future studies on phage-host interactions.

Language: Английский

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Prediction of strain level phage–host interactions across the Escherichia genus using only genomic information

Nature Microbiology, Journal Year: 2024, Volume and Issue: 9(11), P. 2847 - 2861

Published: Oct. 31, 2024

Language: Английский

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TIR signaling activates caspase-like immunity in bacteria

Science, Journal Year: 2025, Volume and Issue: 387(6733), P. 510 - 516

Published: Jan. 30, 2025

Caspase family proteases and Toll/interleukin-1 receptor (TIR)-domain proteins have central roles in innate immunity regulated cell death humans. We describe a bacterial immune system comprising both caspase-like protease TIR-domain protein. found that the TIR protein, once it recognizes phage invasion, produces previously unknown signaling molecule adenosine 5′-diphosphate-cyclo[N7:1′′]-ribose (N7-cADPR). This specifically activates protease, which then indiscriminately degrades cellular to halt replication. The TIR-caspase defense system, we denote as type IV Thoeris, is abundant bacteria efficiently protects against propagation. Our study highlights diversity of TIR-produced molecules demonstrates by caspase an ancient mechanism immunity.

Language: Английский

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