An enterococcal phage protein inhibits type IV restriction enzymes involved in antiphage defense DOI Creative Commons
Nathan P. Bullen, Cydney N. Johnson, Shelby E. Andersen

et al.

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

Published: Aug. 13, 2024

The prevalence of multidrug resistant (MDR) bacterial infections continues to rise as the development antibiotics needed combat these remains stagnant. MDR enterococci are a major contributor this crisis. A potential therapeutic approach for combating is bacteriophage (phage) therapy, which uses lytic viruses infect and kill pathogenic bacteria. While phages that lyse some strains have been identified, other display high levels resistance mechanisms underlying poorly defined. Here, we use CRISPR interference (CRISPRi) screen identify genetic locus found on mobilizable plasmid from Enterococcus faecalis involved in phage resistance. This encodes putative serine recombinase followed by Type IV restriction enzyme (TIV-RE) show restricts replication phi47 vancomycin-resistant E. faecalis. We further find evolves overcome acquiring missense mutation TIV-RE inhibitor protein. inhibitor, termed type inhibiting factor (tifA), binds inactivates diverse TIV-REs. Overall, our findings advance understanding defense drug-resistant provide mechanistic insight into how evolve antiphage systems.

Language: Английский

Bacteria conjugate ubiquitin-like proteins to interfere with phage assembly DOI
Jens Hör, Sharon G. Wolf, Rotem Sorek

et al.

Nature, Journal Year: 2024, Volume and Issue: 631(8022), P. 850 - 856

Published: July 17, 2024

Language: Английский

Citations

18
Towards Standardization of Phage Susceptibility Testing: The Israeli Phage Therapy Center “Clinical Phage Microbiology”—A Pipeline Proposal DOI Open Access
Ortal Yerushalmy,

Ron Braunstein,

Sivan Alkalay‐Oren

et al.

Clinical Infectious Diseases, Journal Year: 2023, Volume and Issue: 77(Supplement_5), P. S337 - S351

Published: Nov. 1, 2023

Abstract Using phages as salvage therapy for nonhealing infections is gaining recognition a viable solution patients with such infections. The escalating issue of antibiotic resistance further emphasizes the significance using in treating bacterial infections, encompassing compassionate-use scenarios and clinical trials. Given high specificity phages, selecting suitable phage(s) targeting causative bacteria becomes critical achieving treatment success. However, contrast to conventional antibiotics, where susceptibility-testing procedures were well established phage therapy, there lack standard frameworks matching from panel target strains assessing their interactions antibiotics or other agents. This review discusses compares published methods microbiology, also known susceptibility testing, proposes guidelines establishing pipeline based on our findings over past 5 years at Israeli Phage Therapy Center.

Language: Английский

Citations

28
Anti-phage defence through inhibition of virion assembly DOI Creative Commons
Pramalkumar H. Patel, Véronique L. Taylor, Chi Zhang

et al.

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

Published: Feb. 22, 2024

Abstract Bacteria have evolved diverse antiviral defence mechanisms to protect themselves against phage infection. Phages integrated into bacterial chromosomes, known as prophages, also encode defences that the hosts in which they reside. Here, we identify a type of anti-phage interferes with virion assembly pathway invading phages. The protein mediates this defence, call Tab (for ‘Tail blocker’), is constitutively expressed from Pseudomonas aeruginosa prophage. allows replication cycle proceed, but blocks tail, thus preventing formation infectious virions. While infected cell dies through activity replicating lysis proteins, there no release progeny, and community thereby protected epidemic. Prophages expressing are not inhibited during their own lytic because express counter-defence function. Thus, our work reveals an operates by blocking assembly, both progeny allowing destruction due expression genes.

Language: Английский

Citations

15
Arbitrium communication controls phage lysogeny through non-lethal modulation of a host toxin–antitoxin defence system DOI

Polina Guler,

Shira Omer Bendori,

Tom Borenstein

et al.

Nature Microbiology, Journal Year: 2024, Volume and Issue: 9(1), P. 150 - 160

Published: Jan. 4, 2024

Language: Английский

Citations

12
High throughput platform technology for rapid target identification in personalized phage therapy DOI Creative Commons
Fereshteh Bayat, Arwa Hilal, Mathura Thirugnanasampanthar

et al.

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

Published: July 11, 2024

Abstract As bacteriophages continue to gain regulatory approval for personalized human therapy against antibiotic-resistant infections, there is a need transformative technologies rapid target identification through multiple, large, decentralized therapeutic phages biobanks. Here, we design high throughput phage screening platform comprised of portable library individual shelf-stable, ready-to-use phages, in all-inclusive solid tablets. Each tablet encapsulates one along with luciferin and luciferase enzyme stabilized sugar matrix pullulan trehalose capable directly detecting phage-mediated adenosine triphosphate (ATP) release ATP bioluminescence reaction upon bacterial cell burst. The composition also enhances desiccation tolerance all components, which should allow easier cheaper international transportation as result, increased accessibility phages. We demonstrate by identifying select multidrug-resistant clinical isolates Pseudomonas aeruginosa , Salmonella enterica Escherichia coli Staphylococcus aureus targets identified within 30-120 min.

Language: Английский

Citations

11
Evolution and ecology of anti-defence systems in phages and plasmids DOI Creative Commons
Théophile Niault, Stineke van Houte, Edze R. Westra

et al.

Current Biology, Journal Year: 2025, Volume and Issue: 35(1), P. R32 - R44

Published: Jan. 1, 2025

Language: Английский

Citations

1
Bacteria- and Phage-Derived Proteins in Phage Infection DOI Creative Commons
О. I. Guliy, Stella S. Yevstigneyeva

Frontiers in Bioscience-Landmark, Journal Year: 2025, Volume and Issue: 30(2)

Published: Feb. 14, 2025

Phages have exerted severe evolutionary pressure on prokaryotes over billions of years, resulting in major rearrangements. Without every enzyme involved the phage–bacterium interaction being examined; bacteriophages cannot be used practical applications. Numerous studies conducted past few years uncovered a huge variety bacterial antiphage defense systems; nevertheless, mechanisms most these systems are not fully understood. Understanding interactions between bacteriophage and proteins is important for efficient host cell infection. Phage bacteriophage–host often arise immediately after Here, we review main groups phage enzymes first stage viral infection responsible degradation membrane. These include polysaccharide depolymerases (endosialidases, endorhamnosidases, alginate lyases, hyaluronate lyases), peptidoglycan hydrolases (ectolysins endolysins). Host target inhibited, activated, or functionally redirected by protein. determine bacteria. Proteins interest holins, endolysins, spanins, which release progeny during lytic cycle. This describes analyzes therapeutic potential bacteriophage-derived proteins.

Language: Английский

Citations

1
Improving phage therapy by evasion of phage resistance mechanisms DOI Creative Commons
Inés Bleriot, Olga Pacios, Lucía Blasco

et al.

JAC-Antimicrobial Resistance, Journal Year: 2023, Volume and Issue: 6(1)

Published: Dec. 28, 2023

Abstract Antibiotic failure is one of the most worrisome threats to global health. Among new therapeutic efforts that are being explored, use bacteriophages (viruses kill bacteria), also known as ‘phages’, extensively studied a strategy target bacterial pathogens. However, main drawbacks phage therapy plethora defence mechanisms bacteria defend themselves against phages. This review aims summarize approaches evaluated overcome systems, including innovative applied: circumvention receptor mutations; modification prophages; targeting CRISPR-Cas systems and biofilm matrix; engineering safer more efficacious phages; inhibition anti-persister strategies used by bacteria.

Language: Английский

Citations

19
Anti-viral defense by an ADP-ribosyltransferase that targets mRNA to block translation DOI Creative Commons
Christopher N. Vassallo, Christopher R. Doering, Michael T. Laub

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Feb. 24, 2024

Abstract Host-pathogen conflicts are crucibles of molecular innovation. Selection for immunity to pathogens has driven the evolution sophisticated mechanisms throughout biology, including in bacteria that must evade their viral predators known as bacteriophages. Here, we characterize a widely distributed anti-phage defense system, CmdTAC, provides robust against infection by T-even family phages. Our results support model which CmdC detects sensing capsid proteins, ultimately leading activation toxic ADP-ribosyltransferase effector protein, CmdT. We show newly synthesized protein triggers dissociation chaperone from CmdTAC complex, destabilization and degradation antitoxin CmdA, with consequent liberation CmdT ADP-ribosyltransferase. Strikingly, does not target DNA, or structured RNA, targets other ADP-ribosyltransferases. Instead, modifies N6 position adenine GA dinucleotides within single-stranded RNAs arrest mRNA translation inhibition replication. work reveals new mechanism anti-viral previously unknown but broadly class ADP-ribosyltransferases mRNA.

Language: Английский

Citations

7
Diverse Antiphage Defenses Are Widespread Among Prophages and Mobile Genetic Elements DOI Creative Commons
Landon J. Getz, Karen L. Maxwell

Annual Review of Virology, Journal Year: 2024, Volume and Issue: 11(1), P. 343 - 362

Published: July 1, 2024

Bacterial viruses known as phages rely on their hosts for replication and thus have developed an intimate partnership over evolutionary time. The survival of temperate phages, which can establish a chronic infection in genomes are maintained quiescent state prophage, is tightly coupled with the bacterial hosts. As result, prophages encode diverse antiphage defense arsenal to protect themselves host they reside from further phage infection. Similarly, success prophage-related elements such phage-inducible chromosomal islands directly tied host, also been shown numerous defenses. Here, we describe current knowledge defenses encoded by mobile genetic elements.

Language: Английский

Citations

6