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      Phage Therapy: What Have We Learned?

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          Abstract

          In this article we explain how current events in the field of phage therapy may positively influence its future development. We discuss the shift in position of the authorities, academia, media, non-governmental organizations, regulatory agencies, patients, and doctors which could enable further advances in the research and application of the therapy. In addition, we discuss methods to obtain optimal phage preparations and suggest the potential of novel applications of phage therapy extending beyond its anti-bacterial action.

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          Most cited references243

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          Programming cells by multiplex genome engineering and accelerated evolution.

          Harris Wang, Farren J. Isaacs, Peter A Carr … (2009)
          The breadth of genomic diversity found among organisms in nature allows populations to adapt to diverse environments. However, genomic diversity is difficult to generate in the laboratory and new phenotypes do not easily arise on practical timescales. Although in vitro and directed evolution methods have created genetic variants with usefully altered phenotypes, these methods are limited to laborious and serial manipulation of single genes and are not used for parallel and continuous directed evolution of gene networks or genomes. Here, we describe multiplex automated genome engineering (MAGE) for large-scale programming and evolution of cells. MAGE simultaneously targets many locations on the chromosome for modification in a single cell or across a population of cells, thus producing combinatorial genomic diversity. Because the process is cyclical and scalable, we constructed prototype devices that automate the MAGE technology to facilitate rapid and continuous generation of a diverse set of genetic changes (mismatches, insertions, deletions). We applied MAGE to optimize the 1-deoxy-D-xylulose-5-phosphate (DXP) biosynthesis pathway in Escherichia coli to overproduce the industrially important isoprenoid lycopene. Twenty-four genetic components in the DXP pathway were modified simultaneously using a complex pool of synthetic DNA, creating over 4.3 billion combinatorial genomic variants per day. We isolated variants with more than fivefold increase in lycopene production within 3 days, a significant improvement over existing metabolic engineering techniques. Our multiplex approach embraces engineering in the context of evolution by expediting the design and evolution of organisms with new and improved properties.
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            Role of mobile DNA in the evolution of vancomycin-resistant Enterococcus faecalis.

            I. T. Paulsen, Jonathan Eisen (2003)
            The complete genome sequence of Enterococcus faecalis V583, a vancomycin-resistant clinical isolate, revealed that more than a quarter of the genome consists of probable mobile or foreign DNA. One of the predicted mobile elements is a previously unknown vanB vancomycin-resistance conjugative transposon. Three plasmids were identified, including two pheromone-sensing conjugative plasmids, one encoding a previously undescribed pheromone inhibitor. The apparent propensity for the incorporation of mobile elements probably contributed to the rapid acquisition and dissemination of drug resistance in the enterococci.
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              The phage abortive infection system, ToxIN, functions as a protein-RNA toxin-antitoxin pair.

              Peter Fineran, Tim R. Blower, Ian J Foulds … (2009)
              Various mechanisms exist that enable bacteria to resist bacteriophage infection. Resistance strategies include the abortive infection (Abi) systems, which promote cell death and limit phage replication within a bacterial population. A highly effective 2-gene Abi system from the phytopathogen Erwinia carotovora subspecies atroseptica, designated ToxIN, is described. The ToxIN Abi system also functions as a toxin-antitoxin (TA) pair, with ToxN inhibiting bacterial growth and the tandemly repeated ToxI RNA antitoxin counteracting the toxicity. TA modules are currently divided into 2 classes, protein and RNA antisense. We provide evidence that ToxIN defines an entirely new TA class that functions via a novel protein-RNA mechanism, with analogous systems present in diverse bacteria. Despite the debated role of TA systems, we demonstrate that ToxIN provides viral resistance in a range of bacterial genera against multiple phages. This is the first demonstration of a novel mechanistic class of TA systems and of an Abi system functioning in different bacterial genera, both with implications for the dynamics of phage-bacterial interactions.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Viruses
                Journal ID (iso-abbrev): Viruses
                Journal ID (publisher-id): viruses
                Title: Viruses
                Publisher: MDPI
                ISSN (Electronic): 1999-4915
                Publication date (Electronic): 28 May 2018
                Publication date Collection: June 2018
                Volume: 10
                Issue: 6
                Electronic Location Identifier: 288
                Affiliations
                [1 ]Bacteriophage Laboratory, Ludwik Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Rudolfa Weigla Street 12, 53-114 Wroclaw, Poland; mbrodzki@ 123456iitd.pan.wroc.pl (R.M.); ewa.jonczyk@ 123456iitd.pan.wroc.pl (E.J.-M.); marzena@ 123456iitd.pan.wroc.pl (M.Ł.-S.); weber@ 123456iitd.pan.wroc.pl (B.W.-D.); natalia.baginska@ 123456iitd.pan.wroc.pl (N.B.); dabrok@ 123456iitd.pan.wroc.pl (K.D.)
                [2 ]Phage Therapy Unit, Ludwik Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Rudolfa Weigla Street 12, 53-114 Wroclaw, Poland; letkiewicz1@ 123456o2.pl
                [3 ]Department of Clinical Immunology, Transplantation Institute, Medical University of Warsaw, Nowogrodzka Street 59, 02-006 Warsaw, Poland; jborysowski@ 123456interia.pl
                [4 ]Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Pawińskiego Street 5 A, 02-106 Warsaw, Poland; lobocka@ 123456ibb.waw.pl (M.Ł.); glowacka@ 123456ibb.waw.pl (A.G.-R.); a.kielan@ 123456ibb.waw.pl (A.B.)
                [5 ]Autonomous Department of Microbial Biology, Faculty of Agriculture and Biology, Warsaw University of Life Sciences, Nowoursynowska Street 159, 02-776 Warsaw, Poland
                [6 ]Medical Sciences Institute, Katowice School of Economics, Harcerzy Września Street 3, 40-659 Katowice, Poland
                [7 ]Research and Development Center, Regional Specialized Hospital, Kamieńskiego 73a, 51-124 Wrocław, Poland
                [8 ]National Institute of Public Health NIZP, Chocimska Street 24, 00-971 Warsaw, Poland; jscheres@ 123456icloud.com
                Author notes
                [* ]Correspondence: agorski@ 123456ikp.pl ; Tel.: +48-71-370-99-05
                [†]

                Current Address: Department of Medical Microbiology, University Medical Centre Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands

                Author information
                https://orcid.org/0000-0002-0863-6041
                https://orcid.org/0000-0001-7379-7290
                Article
                Publisher ID: viruses-10-00288
                DOI: 10.3390/v10060288
                PMC ID: 6024844
                PubMed ID: 29843391
                SO-VID: 0c9d37b7-ea83-47d5-aa94-f9c24b8d3da0
                Copyright © © 2018 by the authors.
                License:

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                Date received : 18 April 2018
                Date accepted : 22 May 2018
                Categories
                Subject: Review

                ScienceOpen disciplines: Microbiology & Virology
                Keywords: phage therapy,experimental therapy,phage cocktails,anti-phage antibodies,prophage,immunomodulation
                Data availability:
                ScienceOpen disciplines: Microbiology & Virology
                Keywords: phage therapy, experimental therapy, phage cocktails, anti-phage antibodies, prophage, immunomodulation

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