Since decades, hardly any novel therapeutic agent against tropical diseases like Malaria, Sleeping sickness or Leishmaniasis came to the market. Additionally, even in the industrial countries the number of infections is steadily increasing, which is especially due to the rapid emergence of resistant microorganisms. Each year, hundreds of millions of people become infected with plasmodia, leishmania, trypanosomes, legionella or resistant staphylococci and candida and a high number of these patients die of the infection. Crucially, the number of resistances against the few chemotherapeutics available drastically increases over the last years. Hence, the search for novel drug compounds with novel mode of actions is of pivotal importance for public health. The major goal of the projects in division A is therefore the preparation, characterization and optimisation of such compounds. Diversified methods of synthesis and analysis as well as a broad conceptual framework ensure the coverage of a wide structural space of chemical substances. Natural producers like plants or marine sponges serve as sources for the isolation of active molecules. To this end, metagenomics is included to search for novel antimicrobial metabolites. Moreover, analogs of natural products are synthesized by classical methods but also by re-combinatorial techniques for the generation of compound libraries. In a second, target-oriented strategy, effector molecules that are designed on a rational basis against defined pathogenicity factors like proteases, fatty acid biosynthesis enzymes or efflux pumps are synthesized.
The goal of the projects in division B is to analyse the molecular interactions between the active compounds and the pathogens or their host systems. The investigations comprise three different levels: the molecular interactions, the cellular interrelations and the interactions observed in whole organisms as exemplified by various animal models. On the cellular level, the inhibitory activity of the compounds is examined for a variety of clinically most relevant pathogenic bacteria, fungi and parasites as well as the cytotoxic effects against human cells. Modern technologies like transcriptomics and proteomics enable the depiction of the detailed mode of action of the active agents on the molecular level. The characterization of the activity of custom-tailored molecules against their specific targets is supported by structural analysis of the complexes revealing the underlying mechanism. Lastly, animal models allow the identification of the overall effect of the compounds on the pathogen in the context of the host’s immune system.
Sophisticated technologies like vibrational spectroscopy, NMR, metabolomics and the bioinformatic analysis of cellular networks are exploited in project division C in order to dissect the molecular mechanism of the active compounds. The drug efficiency and effects in vivo are analysed by NMR imaging of the pathogens in well-established small animal models. The second general route pursued in the SFB is a target-oriented approach toward antimicrobial agents. Based on the three dimensional structure of validated targets in the host, quantum mechanics, molecular modelling, docking and molecular dynamics simulations performed in the C projects allow the design and optimisation of tailor-made inhibitors for chemical synthesis.