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1.
A perfect fit: Bacteriophage receptor-binding proteins for diagnostic and therapeutic applications.
Klumpp, J, Dunne, M, Loessner, MJ
Current opinion in microbiology. 2023;:102240
Abstract
Bacteriophages are the most abundant biological entity on earth, acting as the predators and evolutionary drivers of bacteria. Owing to their inherent ability to specifically infect and kill bacteria, phages and their encoded endolysins and receptor-binding proteins (RBPs) have enormous potential for development into precision antimicrobials for treatment of bacterial infections and microbial disbalances; or as biocontrol agents to tackle bacterial contaminations during various biotechnological processes. The extraordinary binding specificity of phages and RBPs can be exploited in various areas of bacterial diagnostics and monitoring, from food production to health care. We review and describe the distinctive features of phage RBPs, explain why they are attractive candidates for use as therapeutics and in diagnostics, discuss recent applications using RBPs, and finally provide our perspective on how synthetic technology and artificial intelligence-driven approaches will revolutionize how we use these tools in the future.
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2.
Analysis of Spounaviruses as a Case Study for the Overdue Reclassification of Tailed Phages.
Barylski, J, Enault, F, Dutilh, BE, Schuller, MB, Edwards, RA, Gillis, A, Klumpp, J, Knezevic, P, Krupovic, M, Kuhn, JH, et al
Systematic biology. 2020;(1):110-123
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Abstract
Tailed bacteriophages are the most abundant and diverse viruses in the world, with genome sizes ranging from 10 kbp to over 500 kbp. Yet, due to historical reasons, all this diversity is confined to a single virus order-Caudovirales, composed of just four families: Myoviridae, Siphoviridae, Podoviridae, and the newly created Ackermannviridae family. In recent years, this morphology-based classification scheme has started to crumble under the constant flood of phage sequences, revealing that tailed phages are even more genetically diverse than once thought. This prompted us, the Bacterial and Archaeal Viruses Subcommittee of the International Committee on Taxonomy of Viruses (ICTV), to consider overall reorganization of phage taxonomy. In this study, we used a wide range of complementary methods-including comparative genomics, core genome analysis, and marker gene phylogenetics-to show that the group of Bacillus phage SPO1-related viruses previously classified into the Spounavirinae subfamily, is clearly distinct from other members of the family Myoviridae and its diversity deserves the rank of an autonomous family. Thus, we removed this group from the Myoviridae family and created the family Herelleviridae-a new taxon of the same rank. In the process of the taxon evaluation, we explored the feasibility of different demarcation criteria and critically evaluated the usefulness of our methods for phage classification. The convergence of results, drawing a consistent and comprehensive picture of a new family with associated subfamilies, regardless of method, demonstrates that the tools applied here are particularly useful in phage taxonomy. We are convinced that creation of this novel family is a crucial milestone toward much-needed reclassification in the Caudovirales order.
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Taxonomy of prokaryotic viruses: 2018-2019 update from the ICTV Bacterial and Archaeal Viruses Subcommittee.
Adriaenssens, EM, Sullivan, MB, Knezevic, P, van Zyl, LJ, Sarkar, BL, Dutilh, BE, Alfenas-Zerbini, P, Łobocka, M, Tong, Y, Brister, JR, et al
Archives of virology. 2020;(5):1253-1260
Abstract
This article is a summary of the activities of the ICTV's Bacterial and Archaeal Viruses Subcommittee for the years 2018 and 2019. Highlights include the creation of a new order, 10 families, 22 subfamilies, 424 genera and 964 species. Some of our concerns about the ICTV's ability to adjust to and incorporate new DNA- and protein-based taxonomic tools are discussed.
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Bacteriophages: a Panacea in Neuro-Urology?
Leitner, L, Kessler, TM, Klumpp, J
European urology focus. 2020;(3):518-521
Abstract
Bacterial urinary tract infections (UTIs) are very frequent, especially in patients with neurogenic lower urinary tract dysfunction (NLUTD). The steady increase in antibiotic resistance among causative bacteria prompts the search for highly effective therapeutic alternatives with little or no side effects. Bacteriophages - obligate intracellular viruses that solely infect and kill bacteria - are promising tools for treating bacterial infections and have been used for this purpose for almost a century. Recent clinical studies using bacteriophage therapy for UTIs showed encouraging results. In particular, patients with recurrent UTIs, such as individuals with NLUTD who rely on assisted bladder emptying, might benefit from this treatment method. However, bacteriophages are not yet a panacea. More high-quality basic and clinical research on bacteriophage therapy is needed to answer questions on the use of this therapeutic option and its potential to provide a solution to the global threat of multidrug-resistant bacteria. PATIENT SUMMARY Urinary tract infections are very common, especially in patients with neurogenic lower urinary tract dysfunction. In this review we discuss the potential of bacteriophage therapy as an alternative to antibiotics for treating patients with bladder infections.
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5.
Taxonomy of prokaryotic viruses: 2017 update from the ICTV Bacterial and Archaeal Viruses Subcommittee.
Adriaenssens, EM, Wittmann, J, Kuhn, JH, Turner, D, Sullivan, MB, Dutilh, BE, Jang, HB, van Zyl, LJ, Klumpp, J, Lobocka, M, et al
Archives of virology. 2018;(4):1125-1129
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6.
Cross-genus rebooting of custom-made, synthetic bacteriophage genomes in L-form bacteria.
Kilcher, S, Studer, P, Muessner, C, Klumpp, J, Loessner, MJ
Proceedings of the National Academy of Sciences of the United States of America. 2018;(3):567-572
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Abstract
Engineered bacteriophages provide powerful tools for biotechnology, diagnostics, pathogen control, and therapy. However, current techniques for phage editing are experimentally challenging and limited to few phages and host organisms. Viruses that target Gram-positive bacteria are particularly difficult to modify. Here, we present a platform technology that enables rapid, accurate, and selection-free construction of synthetic, tailor-made phages that infect Gram-positive bacteria. To this end, custom-designed, synthetic phage genomes were assembled in vitro from smaller DNA fragments. We show that replicating, cell wall-deficient Listeria monocytogenes L-form bacteria can reboot synthetic phage genomes upon transfection, i.e., produce virus particles from naked, synthetic DNA. Surprisingly, Listeria L-form cells not only support rebooting of native and synthetic Listeria phage genomes but also enable cross-genus reactivation of Bacillus and Staphylococcus phages from their DNA, thereby broadening the approach to phages that infect other important Gram-positive pathogens. We then used this platform to generate virulent phages by targeted modification of temperate phage genomes and demonstrated their superior killing efficacy. These synthetic, virulent phages were further armed by incorporation of enzybiotics into their genomes as a genetic payload, which allowed targeting of phage-resistant bystander cells. In conclusion, this straightforward and robust synthetic biology approach redefines the possibilities for the development of improved and completely new phage applications, including phage therapy.
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Molecular Basis of Bacterial Host Interactions by Gram-Positive Targeting Bacteriophages.
Dunne, M, Hupfeld, M, Klumpp, J, Loessner, MJ
Viruses. 2018;(8)
Abstract
The inherent ability of bacteriophages (phages) to infect specific bacterial hosts makes them ideal candidates to develop into antimicrobial agents for pathogen-specific remediation in food processing, biotechnology, and medicine (e.g., phage therapy). Conversely, phage contaminations of fermentation processes are a major concern to dairy and bioprocessing industries. The first stage of any successful phage infection is adsorption to a bacterial host cell, mediated by receptor-binding proteins (RBPs). As the first point of contact, the binding specificity of phage RBPs is the primary determinant of bacterial host range, and thus defines the remediative potential of a phage for a given bacterium. Co-evolution of RBPs and their bacterial receptors has forced endless adaptation cycles of phage-host interactions, which in turn has created a diverse array of phage adsorption mechanisms utilizing an assortment of RBPs. Over the last decade, these intricate mechanisms have been studied intensely using electron microscopy and X-ray crystallography, providing atomic-level details of this fundamental stage in the phage infection cycle. This review summarizes current knowledge surrounding the molecular basis of host interaction for various socioeconomically important Gram-positive targeting phage RBPs to their protein- and saccharide-based receptors. Special attention is paid to the abundant and best-characterized Siphoviridae family of tailed phages. Unravelling these complex phage-host dynamics is essential to harness the full potential of phage-based technologies, or for generating novel strategies to combat industrial phage contaminations.
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Taxonomy of prokaryotic viruses: 2016 update from the ICTV bacterial and archaeal viruses subcommittee.
Adriaenssens, EM, Krupovic, M, Knezevic, P, Ackermann, HW, Barylski, J, Brister, JR, Clokie, MR, Duffy, S, Dutilh, BE, Edwards, RA, et al
Archives of virology. 2017;(4):1153-1157
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9.
Stable core virome despite variable microbiome after fecal transfer.
Broecker, F, Russo, G, Klumpp, J, Moelling, K
Gut microbes. 2017;(3):214-220
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Abstract
We recently described the 4.5-year time course of the enteric bacterial microbiota and virome of a patient cured from recurrent Clostridium difficile infection (rCDI) by fecal microbiota transplantation (FMT). Here, we extended the virome analyses and found the patient's phage population to exhibit highly donor-similar characteristics following FMT, which remained stable for the whole period tested (up to 7 months). Moreover, the detected viral populations of donor and patient exhibited comparable diversity and richness. These findings were unexpected since enteric viromes are normally highly variable, assumed to influence the bacterial host community and change with environmental conditions. In contrast to the virome, the bacterial microbiota varied indeed for more than 7 months with ongoing dysbiosis before it reached donor similarity. Our findings that are based on sequence information and protein domain analysis seem to suggest that stable phage properties correlate with successful FMT better than the changing bacterial communities. We speculate that we here preferentially detected a stable core virome, which dominated over a variable flexible virome that may have been too heterogeneous for experimental detection or was underrepresented in the databases. It will be interesting to analyze whether the enteric virome allows predictions for the clinical outcome of FMT for rCDI and other diseases such as inflammatory bowel disease or obesity.
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Taxonomy of prokaryotic viruses: update from the ICTV bacterial and archaeal viruses subcommittee.
Krupovic, M, Dutilh, BE, Adriaenssens, EM, Wittmann, J, Vogensen, FK, Sullivan, MB, Rumnieks, J, Prangishvili, D, Lavigne, R, Kropinski, AM, et al
Archives of virology. 2016;(4):1095-9