HZI

Helmholtz-Institute for Pharmaceutical Research Saarland

Partner description - Dr. Alexander Titz, Helmholtz-Institute for Pharmaceutical Research Saarland, Saarbrücken Germany

The Institute (www.helmholtz-hzi.de/HIPS)

Resistance to antibiotics has become one of the major global challenges regarding infectious diseases and is now being tackled by the new Helmholtz-Institute for Pharmaceutical Research Saarland (HIPS). The institute has been founded in August 2009 on the Saarbrücken campus jointly by the Helmholtz Centre for Infection Research (HZI) in Braunschweig and Saarland University, with the goal to contribute to the developing new pharmaceuticals and therapies against infectious diseases. The scientists at HIPS search for novel drugs and improve their application to humans. Hence, HZI systematically extends translation research and thus contributes considerably to the health sciences.

The group

Group Leader: Dr. Alexander Titz (Chemistry), PostDocs: Dr. Stefanie Wagner (Biology), PhD students: MSc Roman Sommer (Chemistry), MSc Ines Joachim (Life Science), MSc Felix Stader (Pharmaceutical Sciences), Technical Assistents: Dirk Hauck (Chemistry), Tamara Paul (Biology), MSc Students: Benjamin Frommeyer (Life Science), David Siebert (Chemistry)

Website: http://www.helmholtz-hzi.de/en/research/research_topics/anti_infectives/ chemical_biology_of_carbohydrates/

Projects in the lab:

Discovery of a novel family of enzymes (GT92) with homologs among parasites

Using a toxicity-based screening system, we have identified a nematode glycosyltransferase (C. elegans GalT-1) which is responsible for the biosynthesis of epitopes recognized by a toxin of fungal immune defense (Butschi et al. PLoS Pathogens 2010, 6(1):e1000717). This enzyme shows an intriguing specificity for its acceptor N-glycan and indicates an additional recognition area remote from the site of catalysis (Titz et al, J. Biol. Chem. 2009, 284(52), 36223). Based on the biochemical data obtained, GalT-1 constitutes the founding member of the novel glycosyltransferase family GT92. The study of the substrate specificity of GalT-1 and its structure in complex with substrates or analogs will yield a detailed understanding of its mechanism. Because a number of GalT-1 homologs exists in parasites, the data may provide therapies for infections with parasites, such as cryptosporidia.

Treatment of chronic infections:disrupting lectin-mediated biofilms

Many human pathogens can establish chronic infections with the help of a biofilm mode of life. As a protective shield, the matrix of the biofilm renders antibiotics ineffective and secures survival of the embedded pathogen. Novel ways for treatment address disintegration of such biofilms and thus restore activity of antibiotics. Frequently, the architecture of biofilms is maintained by carbohydrates and so-called lectins, recognizing and cross-linking carbohydrate motifs of the glycocalyx, both on human cells and pathogens. The inhibition of such structural components leads to the disruption of a biofilm and thereby allows treatment of the infection. Pseudomonas aeruginosa is an important pathogen in hospital-acquired infections and for cystic fibrosis patients. This Gram-negative bacterium can establish chronic infections in various tissues through assembly into protective biofilms. One focus of our research is two P. aeruginosa lectins, which are crucial elements of the biofilm architecture. P. aeruginosa produces two lectins necessary for biofilm formation, which are focus of our research. The group of Dr. Alexander Titz aims at the development of antibacterial drugs using a combination of medicinal chemistry, biochemistry and microbiological methods (see Hauck et al., ACS Chem. Biol. 2013,.8 (8), 1775–1784). Recently, a competitive binding assay was developed for the in vitro evaluation of inhibitors of the Pseudomonas lectins. In collaboration with other groups at HIPS and the HZI, potent molecules obtained by the group are then further evaluated in biofilm and infection models. Such compounds may ultimately lead to successful treatment of chronic infections without evoking resistances among the pathogens.