FOR 854:  Post-genomic Strategies for New Antibiotic Drugs and Targets

• Subject Area: Medicine ; Biology ; Chemistry
• Term: from 2008 to 2017
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 33421847

Antibiotics, more than any other class of medical drugs, have contributed to an increased life expectancy of humans. However, antibacterial resistance has spread globally at an alarming rate and presents a tremendous health threat. Inadequate attention to basic research and development of new drugs has seriously limited treatment options. The objective of the Research Unit is to investigate promising new antibiotic compounds, mechanisms and targets, using post-genome era strategies. The concept is primarily biology-driven and integrates microbiological, biochemical, chemical and pharmaceutical research to identify new antibiotic paradigms.
We are searching for new antibiotic compounds through genome mining and are setting up suitable expression systems for generating variants. A major focus will be on novel antibiotic mechanisms, which can help to overcome the resistance problems. Such mechanisms include promising new targets such as riboswitches and intracellular proteases; for the latter, a highly active new class of antibiotic natural compounds, the acyldepsipeptides, has already been found and will be analysed in detail. In addition, new natural compounds with proven antibiotic activity will be analysed as to interesting new antibiotic mechanisms. A particular focus will be on natural compounds with complex dual or multiple modes of action such as lipopeptide antibiotics.
Since bacterial cell wall biosynthesis is the target pathway for many of these compounds, the impact of antibiotics on the topology and dynamics of the membrane-bound multi-enzyme biosynthesis machinery will be studied to identify new antibiotic activities and new target sites for antibiotic intervention. In one project, we want to directly transfer the generated knowledge into new treatment strategies for parasites by targeting their bacterial endosymbionts.
The history of application of antibiotics has demonstrated that usage is inevitably linked to selection of resistance. Therefore, it will be a permanent task to search for new antibiotic compounds and to study the emerging resistance mechanisms, a topic that has not been adequately addressed for quite some time. It this context, it is one of our main goals to provide excellent training for young scientists towards current challenges and for future development of innovative antibiotic drugs.

• DFG Programme: Research Units

Projects

• Antibiotics of the ADEP and empedopeptin class - Molecular modes of action and studies on bacterial resistance (Applicant Brötz-Oesterhelt, Heike )
• Antibiotics with pleiotropic activities: Daptomycin and amphiphilic glycopeptides (Applicant Schneider, Tanja )
• Biosynthetic and mode of action studies on the nonribosomal peptide antibiotic hormaomycin (Applicant Piel, Jörn )
• Functional Organization of Cell Wall Biosynthesis Reactions in Staphylococci (Applicant Sahl, Hans-Georg )
• Genomic mining for antimicrobial lipopeptides and studies on their biosynthesis (Applicant Groß, Harald )
• Identification of new molecular targets and antibiotics as novel strategies against filaria infections: characterization of lipid II biosynthesis in Wolbachia endobacteria (Applicant Pfarr, Ph.D., Kenneth )
• New bacterial sources for antimicrobially active compounds (Applicant König, Gabriele M. )
• Novel ribosomally synthesized peptide antibiotics from microbial genomes (Applicant Bierbaum, Gabriele )
• Project Administration (Applicant Sahl, Hans-Georg )
• Reconstitution of Bacterial Targets in Model Membranes for a Biosensor-based Functional Analysis and Screening of Antibiotics (Applicant Bendas, Gerd )
• Riboswitches as new antibacterial targets (Applicant Mayer, Günter )

• Spokesperson: Professor Dr. Hans-Georg Sahl
• Deputy: Professorin Dr. Gabriele M. König