TRR261

Zelluläre Mechanismen der Antibiotikawirkung und -produktion

01/07/2019 to 30/06/2023

Over decades we have experienced a dwindling pipeline of new structural scaffolds in antibiotic drug discovery. This is not to the least due to substantial knowledge gaps in fundamental antibiotic research and lack of insight into bacterial cell biology. It became obvious that, even for long-established antibiotics, we often do not understand the cellular consequences of inhibiting a given target, although the direct ligand-target interactions are thoroughly studied. However, it is often the pleiotropic downstream effects following primary target interaction which cause efficient bacterial killing, such as the subsequent deregulation or disintegration of large biosynthetic machineries. Studying antibiotic action on the cellular level will allow us to differentiate potent from less potent antibacterial mechanisms, to elucidate the reasons for synergistic activities between antibiotics, and to explain specificities related to certain species or cell types. Likewise, with regard to antibiotic production, many antibiotic gene clusters and related enzyme functions are known. However, we know little about the localization and physical interactions within biosynthetic production machineries as well as about the physiology of the producer cell in the course of the production process. Studying the functional interplay between the various components of the biosynthetic machinery, its integration into cellular regulatory networks and cross-talk with the primary metabolism, as well as producer stress and adaptations, we aim towards a more rational and efficient production process.
Recent advances in bacterial cell biology have demonstrated the astounding degree of functional organization in bacterial cells, where vital processes require elaborate spatiotemporal control of the components involved. Obviously, antibiotic action and production have to be considered and studied in this context. Modern cell biology has provided technologies to enable such studies as much as antibiotic research can provide valuable inhibitors and tools for bacterial cell biology.
In the TR-CRC ‘Cellular Mechanisms of Antibiotic Action and Production’ (acronym ‘ANTIBIOTIC CellMAP’), we propose to study antibiotic action and antibiotic production side-by-side within living bacteria, yet with a molecular focus. It is our vision to explore the cellular mechanisms of antibiotic action and production in space and time – thereby contributing to an ‘ANTIBIOTIC CellMAP’ – to simultaneously lay a foundation for more rational approaches in antibiotic drug discovery in the future and improve our understanding of fundamental principles of the cellular organization of prokaryotic life.