Project Part Z1
Dr. Tobias Ölschläger, PD Dr. August Stich, Prof. Dr. Dr. Lorenz Meinel
TP Z1 is the central laboratory of the SFB630. It coordinates and standardizes all activities for the identification and evaluation of substances with (probably) antiinfective properties. Many standardized tests were already established during the first funding period. They are now employed and being refined. Reliable growth inhibition tests with various infectious pathogens of the groups bacteria, fungi and parasites represent the basis of the screening program. Quality management was established in order to optimize and further standardize the whole process from the delivery of test substances, the screening experiments, to the final data collection and presentation as well as the feed back communication to the substance providers.
Those substances, which have already been identified during the first funding period to be effective will be the first to be characterized with respect to their uptake pathway, intracellular localization and most importantly their target. This can be achieved by the use of mutants, reporter gene fusions, the array technology, proteomics and new imaging techniques, some of which have been developed in Würzburg. For that purpose E. coli (gram-negative), Staphylococcus aureus (gram-positive), Candida albicans, Trypanosoma brucei and Leishmania major are our model organisms to represent bacteria, fungi and parasites. Besides the in-vitro-assays, testing in animals is scheduled. In these experiments the localization of the pathogen in a (living) animal in the absence and presence of the particular antiinfective substance will be determined by new imaging techniques.
The objective of the TP Z1 will be the screening of substances under standardized criteria. In addition, uptake pathways, intracellular localization, target and mode of action will be elucidated.
TP Z1 has also the resources to stimulate the overall concept of the SFB630 towards the discovery of new drugs against important infectious diseases. Contacts to WHO and the pharmaceutical industry will help to fuel this target-oriented approach.
Selected, SFB-relevant Publications
A. Stich, A. Ponte-Sucre, U. Holzgrabe; Do we need new drugs against human African trypanosomiasis? Lancet Inf Diseases 2013, 13, 733-734. doi:doi:10.1016/S1473-3099(13)70191-9
G. Hiltensperger, N. G. Jones, S. Niedermeier, A. Stich, M. Kaiser, J. Jung, S. Puhl, A. Damme, H. Braunschweig, L. Meinel, M. Engstler, U. Holzgrabe; Synthesis and structure-activity relationships of new quinolone-type molecules against Trypanosoma brucei. J Med Chem 2012, 55, 2538-2548.
L. Glans, W. Hu, C. Jost, C. de Kock, P. J. Smith, M. Haukka, H. Bruhn, U. Schatzschneider, E. Nordlander; Synthesis and biological activity of cymantrene and cyrhetrene 4-aminoquinoline conjugates against malaria, Leishmaniasis, and trypanosomiasis. Dalton Trans 2012, 41, 6443-6450.
G. Bringmann, G. Zhang, T. Olschlager, A. Stich, J. Wu, M. Chatterjee, R. Brun; Highly selective antiplasmodial naphthylisoquinoline alkaloids from Ancistrocladus tectorius. Phytochemistry 2012.
T. M. Menzel, M. Tischer, P. Francois, J. Nickel, J. Schrenzel, H. Bruhn, A. Albrecht, L. Lehmann, U. Holzgrabe, K. Ohlsen; Mode-of-action studies of the novel bisquaternary bisnaphthalimide MT02 against Staphylococcus aureus. Antimicrob Agents Chemother 2011, 55, 311-320.
L. Liu, T. Bruhn, L. Guo, D. C. Gotz, R. Brun, A. Stich, Y. Che, G. Bringmann; Chloropupukeanolides C-E: cytotoxic pupukeanane chlorides with a spiroketal skeleton from Pestalotiopsis fici. Chemistry 2011, 17, 2604-2613.
G. Harms, H. Scherbaum, I. Reiter-Owona, A. Stich, J. Richter; Treatment of imported New World cutaneous Leishmaniasis in Germany. Int J Dermatol 2011, 50, 1336-1342.
V. Ehmke, C. Heindl, M. Rottmann, C. Freymond, W. B. Schweizer, R. Brun, A. Stich, T. Schirmeister, F. Diederich; Potent and selective inhibition of cysteine proteases from Plasmodium falciparum and Trypanosoma brucei. ChemMedChem 2011, 6, 273-278.
A. Cecil, C. Rikanovic, K. Ohlsen, C. Liang, J. Bernhardt, T. A. Oelschlaeger, T. Gulder, G. Bringmann, U. Holzgrabe, M. Unger, T. Dandekar; Modeling antibiotic and cytotoxic effects of the dimeric isoquinoline IQ-143 on metabolism and its regulation in Staphylococcus aureus, Staphylococcus epidermidis and human cells. Genome Biol 2011, 12, R24.
G. Bringmann, B. Hertlein-Amslinger, I. Kajahn, M. Dreyer, R. Brun, H. Moll, A. Stich, K. N. Ioset, W. Schmitz, L. H. Ngoc; Phenolic analogs of the N,C-coupled naphthylisoquinoline alkaloid ancistrocladinium A, from Ancistrocladus cochinchinensis (Ancistrocladaceae), with improved antiprotozoal activities. Phytochemistry 2011, 72, 89-93.
M. Xu, T. Bruhn, B. Hertlein, R. Brun, A. Stich, J. Wu, G. Bringmann; Shuangancistrotectorines A-E, dimeric naphthylisoquinoline alkaloids with three chiral biaryl axes from the Chinese plant Ancistrocladus tectorius. Chemistry 2010, 16, 4206-4216.
T. Waag, C. Gelhaus, J. Rath, A. Stich, M. Leippe, T. Schirmeister; Allicin and derivates are cysteine protease inhibitors with antiparasitic activity. Bioorg Med Chem Lett 2010, 20, 5541-5543.
G. Fan, Z. Li, S. Shen, Y. Zeng, Y. Yang, M. Xu, T. Bruhn, H. Bruhn, J. Morschhauser, G. Bringmann, W. Lin; Baculiferins A-O, O-sulfated pyrrole alkaloids with anti-HIV-1 activity, from the Chinese marine sponge Iotrochota baculifera. Bioorg Med Chem 2010, 18, 5466-5474.
G. Bringmann, S. K. Bischof, S. Muller, T. Gulder, C. Winter, A. Stich, H. Moll, M. Kaiser, R. Brun, J. Dreher, K. Baumann; QSAR guided synthesis of simplified antiplasmodial analogs of naphthylisoquinoline alkaloids. Eur J Med Chem 2010, 45, 5370-5383.
A. Breuning, B. Degel, F. Schulz, C. Buchold, M. Stempka, U. Machon, S. Heppner, C. Gelhaus, M. Leippe, M. Leyh, C. Kisker, J. Rath, A. Stich, J. Gut, P. J. Rosenthal, C. Schmuck, T. Schirmeister; Michael acceptor based antiplasmodial and antitrypanosomal cysteine protease inhibitors with unusual amino acids. J Med Chem 2010, 53, 1951-1963.
J. Verdon, M. Falge, E. Maier, H. Bruhn, M. Steinert, C. Faber, R. Benz, Y. Hechard; Detergent-like activity and alpha-helical structure of warnericin RK, an anti-Legionella peptide. Biophys J 2009, 97, 1933-1940.
K. Ohlsen, T. A. Oelschlaeger, J. Hacker, A. S. Khan; Carbohydrate receptors of bacterial adhesins: implications and reflections. Top Curr Chem 2009, 288, 17-65.
M. Altenkamper, B. Bechem, J. Perruchon, S. Heinrich, A. Madel, R. Ortmann, H. M. Dahse, E. Freunscht, Y. Wang, J. Rath, A. Stich, M. Hitzler, P. Chiba, M. Lanzer, M. Schlitzer; Antimalarial and antitrypanosomal activity of a series of amide and sulfonamide derivatives of a 2,5-diaminobenzophenone. Bioorg Med Chem 2009, 17, 7690-7697.
M. Muth, V. Hoerr, M. Glaser, A. Ponte-Sucre, H. Moll, A. Stich, U. Holzgrabe; Antitrypanosomal activity of quaternary naphthalimide derivatives. Bioorg Med Chem Lett 2007, 17, 1590-1593.
R. Vicik, V. Hoerr, M. Glaser, M. Schultheis, E. Hansell, J. H. McKerrow, U. Holzgrabe, C. R. Caffrey, A. Ponte-Sucre, H. Moll, A. Stich, T. Schirmeister; Aziridine-2,3-dicarboxylate inhibitors targeting the major cysteine protease of Trypanosoma brucei as lead trypanocidal agents. Bioorg Med Chem Lett 2006, 16, 2753-2757.
V. Hoerr, A. Stich, U. Holzgrabe; Critical aspects of analysis of Micrococcus luteus, Neisseria cinerea, and Pseudomonas fluorescens by means of capillary electrophoresis. Electrophoresis 2004, 25, 3132-3138.
G. Bringmann, V. Hoerr, U. Holzgrabe, A. Stich; Antitrypanosomal naphthylisoquinoline alkaloids and related compounds. Pharmazie 2003, 58, 343-346.