Infections with the often multi-resistant pathogen Achromobacter xylosoxidans are reported more and more frequently. This opportunistic pathogen is for example involved in cystic fibrosis, a metabolic disorder for which no cure exists. Bacteriophages (phages for short) are natural enemies of bacteria and might provide an alternative way of effectively fighting infections, in particular hospital-acquired infections. Johannes Wittmann, a researcher at Leibniz Institute DSMZ – German Collection of Microorganisms and Cell Cultures, Braunschweig (Brunswick), Germany, has isolated and thoroughly studied various phages targeting Achromobacter xylosoxidans. His is the first study presenting a large number of diverse phages that might be used to fight this pathogen. Further studies investigating their therapeutic potential are under way. Initial results have just been published in the scientific journals PLOS One and Virology Journal.
Viruses targeting bacteria are referred to as bacteriophages, or phages for short. They have become a focus of scientific interest for rather practical reasons: As antibiotics are losing, at an alarming rate, their effectiveness in fighting multi-resistant bacterial pathogens, these natural enemies of bacteria are becoming more and more important. This is where current basic research at DSMZ, conducted by a team led by scientists Johannes Wittmann and Christine Rohde, comes into play.
“As the name bacteriophages (which is derived from the Greek ‘phagos,’ meaning ‘glutton’) suggests, these viruses ‘devour’ bacteria, effectively destroying them,” as Johannes Wittmann, a postdoctoral researcher at DSMZ, explains. “They achieve this by using a sophisticated system. The virus injects its genetic material into the bacterial cell where it is ‘read’ by the protein-making mechanisms of the bacterium, essentially reprogramming it. In this way, the phages, like tiny pirates, ‘hijack’ the bacterial cell.
The result is the production of countless new phages. Eventually, the host cell bursts, releasing hundreds of these viruses, which in turn may destroy more bacteria.”
A new strategy for battling multi-resistant pathogens
This effective mechanism of action employed by phages, plus the fact that they are harmless to humans, might make bacteriophages a weapon in the fight against various multi-resistant infectious agents. “Phages are particularly suited to fighting pathogens because they each target only one specific species of host bacteria,” says Johannes Wittmann. “You might think of them as ‘intelligent’, self-limiting medications. They will replicate only at the site of bacterial infection, and they will do so only until all host bacteria have been used up.”
At the center of this first comprehensive scientific study of phages at DSMZ is the mobile gram-negative rod-shaped bacterium Achromobacter xylosoxidans, an opportunistic pathogen that so far has not been sufficiently investigated. Achromobacter xylosoxidans is wide spread in our natural environment, occurring both in soil and various water sources. While often harmless, it may cause severe infections, such as endocarditis, bacteriemia, and meningitis, in people with compromised immune systems.
“In medicine, the often multi-resistant pathogen Achromobacter plays a not to be ignored role in cystic fibrosis, a tragic metabolic disorder for which no cure exists today,” says Johannes Wittmann. “In patients with cystic fibrosis, this bacterium is one of several species forming biofilms in the affected lungs. These biofilms are more accessible to phages than to antibiotics. It is just these opportunistic pathogens that have hospital staff worried. We therefore consulted on this project with Charité, the Berlin university hospital.”
“We are seeing an increase in patients with opportunistic infections in recent years,” comments Professor Martin Witzenrath of the Department of Infectious Diseases and Respiratory Medicine at Charité. “In this context, pathogens that are resistant to common antibiotics such as penicillin, macrolides, and cephalosporins, present us with major therapeutic challenges. From a clinical point of view, Achromobacter is problematic as well, in particular in patients with cystic fibrosis, and we fear that we will see it much more often in the future. This illustrates an urgent unmet need for fighting pathogens that are resistant to antibiotics. Wittmann’s current study presents an important example of a new alternative strategy.”
New phages targeting Achromobacter
“Phages are best found in the same places that are inhabited by the pathogens that we suspect them to be effective against, e.g., in waste water. We have been able to readily isolate phages targeting Achromobacter from municipal water treatment plants. For screening purposes, we incubated filtrates from the plant with the host bacteria,” recalls Johannes Wittmann. “Plaques forming in the bacterial lawn on the agar plates then showed us where we would find the matching phages.”
A widely diverse range of more than 60 strains of the genus Achromobacter was used as host bacteria. They were taken from the DSMZ’s own collection as well as from culture collections in Sweden, the Czech Republic, Belgium, and Canada. Most of the strains had been isolated from clinical samples such as sputum, blood, and urine, or from the environment. They all exhibited resistance to antibiotics commonly used in hospitals.
A total of 34 phages were isolated and characterized, and some of their genetic material has already been sequenced at DSMZ. “We were very surprised to discover that two phages belong to the rare family of N4-like phages,” says Wittmann.
“More studies are needed to test Achromobacter targeting phages for their usefulness as therapeutic phages. Then they would be added to the collection of therapeutic phages at DSMZ,” explains Christine Rohde, head of the working group. “These studies include the sequencing of the entire phage genome in order to exclude genes encoding for undesirable properties.”
The Phage Collection at DSMZ:
The specialized phage collection currently contains about 350 phages targeting a wide range of bacteria. Phages are of interest to humans because they are so closely associated with (and limited to) their individual bacterial hosts. Thus, they can be used to fight harmful bacteria, with applications in animal husbandry, agriculture, food production, and medical therapy.
DSMZ information on phages online:
DSMZ offers information on phages and their therapeutical use online at: https://www.dsmz.de/home/info-on-phages.html
J. Wittmann et al.: Isolation and Characterization of Numerous Novel Phages Targeting Diverse Strains of the Ubiquitous and Opportunistic Pathogen Achromobacter xylosoxidans. PLOSone (2014) http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0086935
J. Wittmann et.al : First genome sequences of Achromobacter phages reveal new members of the N4 family. Virology Journal 2014, 11:14 http://www.virologyj.com/content/11/1/14
C. Rohde & J. Sikorski: Bakteriophagen – Vielfalt, Anwendung und ihre Bedeutung für die Wissenschaft vom Leben. Naturwiss. Rundschau (2011) 751, 5 – 14 (in German)
J. Garbe et al. (2010): Characterization of JG024, a pseudomonas aeruginosa PB1-like broad host range phage under simulated infection conditions. BMC Microbiology 2010, 10:301 doi:10.1186/1471-2180-10-301
L. Kvachadze et al.: Evaluation of lytic activity of staphylococcal bacteriophage Sb-1 against freshly isolated clinical pathogens. Microbial Biotechnol. (2011) 4(5), 643-650
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About the Leibniz Institute DSMZ
The Leibniz Institute DSMZ – German Collection of Microorganisms and Cell Cultures GmbH is a Leibniz Association institution. Offering comprehensive scientific services and a wide range of biological materials, it has been a partner for research and industry organizations worldwide for decades. DSMZ is one of the largest biological resource centers of its kind to be compliant with the internationally recognized quality norm ISO 9001:2008. As a patent depository, DSMZ currently offers the only option in Germany of accepting biological materials according to the requirements of the Budapest Treaty. The second major function of DSMZ, in addition to its scientific services, is its collection-related research. The Brunswick (Braunschweig), Germany, based collection has existed for 44 years and holds more than 49,000 cultures and biomaterials. DSMZ hosts the most diverse collection worldwide: In addition to fungi, yeasts, bacteria, and archaea, it is home to human and animal cell cultures, plant viruses, and plant cell cultures that are archived and studied there. www.dsmz.de
The Leibniz Association connects 89 independent research institutions that range in focus from the natural, engineering and environmental sciences via economics, spatial and social sciences to the humanities. Leibniz institutes address issues of social, economic and ecological relevance. They conduct knowledge-driven and applied basic research, maintain scientific infrastructure and provide research-based services. The Leibniz Association identifies focus areas for knowledge transfer to policy-makers, academia, business and the public. Leibniz institutions collaborate intensively with universities – in the form of “WissenschaftsCampi” (thematic partnerships between university and non-university research institutes), for example – as well as with industry and other partners at home and abroad. They are subject to an independent evaluation procedure that is unparalleled in its transparency. Due to the importance of these institutions for the country as a whole, they are funded jointly by the Federation and the Länder, employing some 16,500 individuals, including 7,700 researchers. The entire budget of all the institutes is approximately 1.4 billion EUR.