Figure 1. Crystal structure of the endolysin PlyPSA with the cell wall binding domain (CBD) in blue, and the enzymatically active domain (EAD) in red(7, 8). The proteins are separated by a short linker in purple. CBDs and EADs are easily interchangeable between endolysins. By creating chimeric endolysins new highly effective variants can be found.
Figure 1. Crystal structure of the endolysin PlyPSA with the cell wall binding domain (CBD) in blue, and the enzymatically active domain (EAD) in red(7, 8). The proteins are separated by a short linker in purple. CBDs and EADs are easily interchangeable between endolysins. By creating chimeric endolysins new highly effective variants can be found.
 

Our research currently focuses on the development of novel protein-based antibiotics to be used as a remedy for patients suffering from bacterial infections. There is an urgent need for new treatments against antibiotic resistant bacteria(1–3). At the same time, less harmful infections, that have previously been treated with traditional small molecular antibiotics, could be treated with new alternatives to reduce the overall small molecular antibiotic usage. Protein-based antibiotics are an interesting alternative, both to be used routinely to lower the overall small molecular antibiotic usage, and as a therapy of last resort. Of particular interest are endolysins.

Endolysins are protein-based enzymes that are able to degrade the cell wall of gram positive bacteria and lyse them(4, 5). They originate from viruses (bacteriophages, phages) that attack and live on bacteria. Phages are using endolysins to escape the bacteria after proliferation. In addition, there are a variety of other enzymes which exert the same lytic effect, but are derived from sources other than phages. These are generally called lysins.

By isolating new phages from environmental sources(6) we are able to obtain the DNA sequence which encodes for the endolysin. The endolysins can be produced with common molecular biology methods and engineered to suit our purposes.

We have a particular interest in developing new tools for endolysin engineering, and to use endolysins as the foundation when developing novel protein-based antibiotics. These research projects have the potential to lead to novel antibiotics that can treat patients with resistant bacterial infections as well as replace small molecular antibiotics in less severe infections.

There are several companies pursuing drug development of endolysin based treatments out of which some have reached clinical trials. See videos below from some of these companies.

 

 

 

 

 

 

Please contact us if you are interested in performing an internship, master thesis project, PhD or postdoc.

 

1. de Kraker MEA, Davey PG, Grundmann H. 2011. Mortality and hospital stay associated with resistant Staphylococcus aureus and Escherichia coli bacteremia: Estimating the burden of antibiotic resistance in Europe. PLoS Med 8.

2. Levy SB, Marshall B. 2004. Antibacterial resistance worldwide: causes, challenges and responses. NatMed 10:S122–S129.

3. Bassetti M, Merelli M, Temperoni C, Astilean A. 2013. New antibiotics for bad bugs: where are we? Ann Clin Microbiol Antimicrob 12:1.

4. Nelson DC, Schmelcher M, Rodriguez-Rubio L, Klumpp J, Pritchard DG, Dong S, Donovan DM. 2012. Endolysins as AntimicrobialsAdvances in Virus Research, 1sted. Elsevier Inc.

5. Fischetti VA. 2010. Bacteriophage endolysins: A novel anti-infective to control Gram-positive pathogens. Int J Med Microbiol 300:357–362.

6. Khan Mirzaei M, Nilsson AS. 2015. Isolation of phages for phage therapy: A comparison of spot tests and efficiency of plating analyses for determination of host range and efficacy. PLoS One 10:1–13.

7. Korndörfer IP, Danzer J, Schmelcher M, Zimmer M, Skerra A, Loessner MJ. 2006. The crystal structure of the bacteriophage PSA endolysin reveals a unique fold responsible for specific recognition of Listeria cell walls. J Mol Biol 364:678–89.

8. Pettersen EF, Goddard TD, Huang CC, Couch GS, Greenblatt DM, Meng EC, Ferrin TE. 2004. UCSF Chimera — A Visualization System for Exploratory Research and Analysis.