TRR 261:  Cellular Mechanisms of Antibiotic Action and Production

• Subject Area: Medicine ; Biology ; Chemistry
• Term: from 2019 to 2024
• Website: Homepage
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 398967434

In our TRR ‘Cellular Mechanisms of antibiotic Action and Production’ (acronym ‘antibiotic CellMAP’), we study antibiotic activities in bacterial target cells (project area A) and antibiotic biosynthesis in bacterial producer cells (project area B). Bacterial producer cells have evolved diverse strategies to protect themselves from the damage they cause in bacterial target cells. Therefore, the two project areas benefit each other, and many of the projects proposed for the second funding period explore aspects of both project areas. A hallmark of CellMAP is the strong interest in the cell biology and physiology of bacteria exposed to antibiotics. All projects have a clear cellular focus, asking questions on antibiotic action and production that cannot be answered by molecular in vitro experiments alone. While studying the damage inflicted by antibiotics, we acknowledge the structural and metabolic complexity of the target cells. We consider primary and secondary targets, immediate and downstream effects, interference with the cellular organization in space and time, adjustment of metabolite fluxes, protective stress responses, and emerging mutations. In producer cells, when contemplating why and how specific antibiotics are produced, we consider metabolic burden, access to precursors, the interaction of the biosynthetic machineries, and the biological function of the products. We create thematic synergy by orienting our research toward certain focus topics. Many antibiotics affect the cell envelope, and we study their impact on cell envelope integrity and function. Large biosynthetic ‘mega’-complexes drive antibiotic biosynthesis and others are pivotal antibiotic targets, and we study the spatiotemporally coordinated activities of those complexes and their dysorganization by antibiotics. Regulatory signals and circuits, their dysregulation by antibiotics, and adaptation processes to re-establish cellular function are recurrent themes in many projects. In the second funding period, we will explore the two further focus topics, ‘protection against antibiotic action’ and ‘antibiotic interactions - synergism/antagonism’, to increase fundamental knowledge in two areas of paramount importance in the antibiotic field: rising antibiotic resistance and the demand for antibiotic combination therapy. In the second funding period, we will enter the next stage in exploring our ‘antibiotic CellMAP’ in the literal sense of understanding the complex network of antibiotic action and production in bacterial cells. We study, e.g., related agents, targets with specific differences, inhibitors versus activators of the same target, gene cluster cross-talk, metabolite patterns and fluxes, regulatory circuits, and proteome-wide side effects. CellMAP performs fundamental research. We aim to contribute to the knowledge base essential in antibiotic discovery while gaining further insight into the fundamental principles of prokaryotic life.

• DFG Programme: CRC/Transregios

Current projects

• A01 - Physiological impact of ClpP modulators on bacteria and mitochondria (Project Head Brötz-Oesterhelt, Heike )
• A07 - Molecular characterization of lipid II pathway inhibitor-induced persistence phenotypes in Chlamydia and Wolbachia (Project Head Henrichfreise, Beate )
• A09 - Role of the VraDE transporter in differential susceptibility of S. aureus towards guanidine-containing lipopeptides and other cell wall targeting antibiotics (Project Heads Geyer, Matthias ;  Groß, Harald ;  Schneider, Tanja )
• A10 - From primary target inhibition to collapse of the cell envelope biosynthetic network (Project Head Schneider, Tanja )
• A11 - The role of lipid II accumulation in the mode of action of glycopeptide antibiotics (Project Heads Grein, Fabian ;  Kubitscheck, Ulrich )
• B05 - Adaptation mechanisms of actinomycetes to the production of a variety of antibiotics (Project Heads Stegmann, Ph.D., Efthimia ;  Ziemert, Nadine )
• B06 - Enzyme cooperativity in the biosynthesis of antibiotics and their cellular target structures (Project Head Dickschat, Jeroen )
• B07 - Double bond shifts and biosynthetic mega-complex analysis of vancoresmycin (Project Head Menche, Dirk )
• Z01 - Chemical analyses, isolation, and syntheses of antibiotics (Project Heads Grond, Stephanie ;  Hughes, Ph.D., Chambers ;  Menche, Dirk )
• Z02 - Advanced microscopy techniques (Project Heads Endesfelder, Ulrike ;  Kubitscheck, Ulrich ;  Oesterhelt, Filipp ;  Sass, Peter )
• Z03 - Multi-OMICs analyses and integrative data management (Project Heads Kohlbacher, Oliver ;  Macek, Boris ;  Nahnsen, Sven ;  Nieselt, Kay Katja )
• Z04 - Central administration, coordination, and future development of the Collaborative Research Center (Project Head Brötz-Oesterhelt, Heike )

Completed projects

• A02 - Disturbing bacterial morphogenesis by antibiotic action (Project Head Sass, Peter )
• A03 - Impact of carba-glucosamine on bacterial cell metabolism (Project Head Mayer, Günter )
• A04 - Mode of action of rhodomyrtone (Rom) and synthesized derivatives and studying the resistance mechanism mediated by FarE / FarR (Project Heads Götz, Friedrich ;  Maier, Martin E. )
• A06 - Cellular responses to the antibiotic fosfomycin. (Project Head Mayer, Christoph )
• A08 - Mode of action of cell wall biosynthesis inhibitors in Wolbachia spp. (Project Head Pfarr, Ph.D., Kenneth )
• B01 - Spatial and temporal cellular assembly of the glycopeptide biosynthetic complex (Project Heads Stegmann, Ph.D., Efthimia ;  Wohlleben, Wolfgang )
• B02 - Functional dissection of transport processes during glycopeptide antibiotic production (Project Head Wagner, Ph.D., Samuel )
• B03 - Cellular responses to heterologously expressed antibiotic gene clusters (Project Heads Gust, Bertolt ;  Kaysser, Leonard )
• B04 - Horizontal transfer, evolution, and cellular integration of Staphylococcus antibiosis islands (SAbIs) (Project Heads Heilbronner, Simon ;  Peschel, Andreas )
• B08 - Structures of cellular machineries relevant for antibiotic synthesis and action (Project Head Stehle, Thilo )

• Applicant Institution: Eberhard Karls Universität Tübingen
• Co-Applicant Institution: Rheinische Friedrich-Wilhelms-Universität Bonn
• Spokesperson: Professorin Dr. Heike Brötz-Oesterhelt