Phage diversity for research and application

PI: Dr. Christine Rohde, Dr. Johannes Wittmann

The occurrence of multiple antibiotic resistant and even pan-resistant bacteria has dramatically risen and developed to one of the most serious global public health concerns, particularly in human and veterinary medicine. Due to their abundance and opportunistic pathogenicity, bacterial species like Acinetobacter baumanniiPseudomonas aeruginosa or Staphylococcus aureus, among others, have become a dangerous threat especially for hospitalized or chronically infected patients and alternatives to antibiotics are urgently needed to overcome severe infections. Bacteriophages (short: phages) are one if not the most promising of those alternatives. Phages have been successfully used to fight bacterial infections in Eastern Europe for decades with convincing results. To foster the re-introduction of phage therapy in Germany and more generally, in the West, the DSMZ phage group – together with clinical partners and the Fraunhofer Institute for Toxicology and Experimental Medicine in Braunschweig and Hannover- is currently involved in different research projects and studies dealing with the implementation of phages for application in human medicine, see below. Main tasks in those projects include 1., provision of phages from the open DSMZ collection and isolating new phages for the goals of the projects to expand the panels of species-specific phage diversity. We aim at collecting such phage diversity per bacterial species for obtaining finally broad strain coverages. 2., investigation of different aspects of phage biology including host spectra, phage efficiency parameters, phage morphology, phage genomics etc. 

Currently running consortial projects, both under consultancy with the German licensing authority BfArM, Bonn:

  • Phage4Cure (http://phage4cure.de/de/), the first German publicly funded project aiming at a clinical trial with the development of purified phages as inhalative therapy against Pseudomonas aeruginosa in bronchiectasis. Phage4Cure is the first scientific study applying licensed GMP preparations containing phages as active pharmaceutical ingredients (APIs) in Germany. Project start: September 2017, duration of project: 3 years, funding 100% by the BMBF, project partners: Leibniz-Institute DSMZ, Fraunhofer ITEM (Coordinator), Charité University hospital Berlin, Charité Research Organisation GmbH Berlin.
  • PhagoFlow (website under construction), the first German publicly funded practicability testing project for the magistral use of GMP-purified phage preparations against prioritized bacteria of the ESKAPE group. In contrast to a clinical trial, PhagoFlow will apply individualized combinations of efficiently working phages in single patient cases, predominantly in deep infected wounds where antibiotics have failed. A sustainable routine method for applying phagograms in hospital diagnostic labs will be developed to determine the most efficient phage mixture per patient. Project start: April 2019, duration of project: 3 years, funding 100% by Innovationsausschuss des Gemeinsamen Bundesausschusses, project partners: Leibniz-Institute DSMZ, Fraunhofer ITEM, Bundeswehrkrankenhaus Berlin (Coordinator),
  • PhagoMed Biopharma GmbH (https://www.phagomed.com), a biotech company located in Vienna focusses on bacteriophage to overcome infections by antibiotic-resistant bacteria. The DSMZ amongst other research groups acts as a collaboration partner to examine the potential of phages and to develop three different phage-based drugs, in particular in the field of infected artificial joints.

Apart from research aspects regarding probable application, novel sequencing methods led to a boost of available sequence data during the last years. By isolating novel phages and using sequence data and different tools for analysis like VICTOR (developed at the DSMZ), we also aim at getting more insight into the diversity of phages, pushing forward the viral taxonomy under the umbrella of the International Committee on Taxonomy of Viruses (ICTV) and providing those for the whole phage researcher community. For this purpose, some years ago the DSMZ phage group started the Phage Trapper Project, in which students from the TU Braunschweig learn how to isolate and characterize phages against different host organisms. In the meantime, several German universities have also already contributed to that project by depositing phages from similar projects.

Selected references:

  1. Korf IHE, Meier-Kolthoff JP, Adriaenssens EM, Kropinski AM, Nimtz M, Rohde M, van Raaij MJ, WittmannJStill Something to Discover: Novel Insights intoEscherichia coliPhage Diversity and Taxonomy.Viruses. 2019 May 17;11(5). pii: E454. doi: 10.3390/v11050454.
  2. RohdeC, WittmannJ,Kutter E (2018) Bacteriophages: A Therapy Concept against Multi-Drug-Resistant Bacteria. Surg Infect (Larchmt). 19:737-744. doi: 10.1089/sur.2018.184. 
  3. Sybesma W, Rohde C, Bardy P, Pirnay JP, Cooper I, Caplin J, Chanishvili N, Coffey A, De Vos D, Scholz AH, McCallin S, Püschner HM, Pantucek R, Aminov R, Doškař J, Kurtbӧke Dİ (2018) Expert round table on acceptance and re-implementation of bacteriophage therapy. Silk Route to the Acceptance and Re-Implementation of Bacteriophage Therapy-Part II. Antibiotics (Basel). 7(2). pii: E35. doi: 10.3390/antibiotics7020035.