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SFB 766:  The Bacterial Cell Envelope: Structure, Function and Infection Interface

Subject Area Medicine
Biology
Chemistry
Term from 2007 to 2019
Project identifier Deutsche Forschungsgemeinschaft (DFG) - Project number 32152271
 
Final Report Year 2019

Final Report Abstract

The bacterial envelope determines the shape, surface properties, and solute permeability of bacteria. More- over, it serves as a barrier by which bacteria interact and communicate with each other and the environment thereby exerting a decisive function in bacterial physiology, morphogenesis, transport, and sensitivity or re- sistance towards antimicrobial agents as well as in biotechnological processes. In pathogens, the bacterial surface plays a crucial role in infections and elicits immune reactions. The cell envelope consists of the cyto- plasmic membrane, the cell wall with its appendages, and, in case of Gram-negative bacteria, the outer membrane. Due to its chemical and structural complexity and diversity, insight into the molecular details of bacterial envelopes was rather limited when the CRC766 started in 2007. The biosynthesis of the three- dimensional network of the cell wall, its highly dynamic properties, and its role in both bacterial physiology and bacteria-host interaction were only poorly understood. Work of the CRC on the bacterial cell envelope was initiated because of two reasons. On one hand Tübingen had a long-standing tradition in research into various aspects of the bacterial cell envelope. Besides others Wolfhard Weidel, Joachim Höltje and Volkmar Braun had performed pioneering work on the structure and function of the bacterial envelope. However, research in this field has come to a certain stand still thereafter due to the lack of suitable technologies for investigating the cell envelope in more depth. But, on the other hand, the new –omics technologies, improved analytical methods, progress in structural biology and bioin- formatics offered a great chance to continue with cell envelope research at a new level. Research in this CRC was dedicated to expanding our understanding of the structure, function, and biosyn- thesis of the bacterial cell envelope in an interdisciplinary approach. Furthermore, interactions of the cell envelope with the environment and with the host, its contribution to pathogenicity, and its role in the mode of action of new antibiotics as well as in antibiotic resistance were investigated. These aspects were studied in a broad range of bacteria covering major model organisms as well as important human pathogens. The CRC was structured in two sections, Section A was focused on the synthesis, turnover and function of components of the bacterial cell envelope: by analysing cell wall synthesis and structure we could show among others that cell wall turnover is a permanent, dynamic process which can be targeted by antibiotics, that nanopores in septa of filamentous bacteria are required for cell-cell communication, and are equipped with gates which control closing and opening these pores. Research on antibiotic producing bacteria made it possible to characterize and optimize antibiotics by analysing their biosynthesis and their interaction with cell wall associated enzymes. Furthermore, we could show that gene transfer across streptomycete cell walls is mediated by a process resembling chromosome segregation enabling the horizontal transfer of large DNA fragments; a process which is highly relevant for the evolution of antibiotic biosynthesis gene cluster and associated enzymes. Pioneering research revealed that not only the well-known antibiotic producers such as actinobacteria are able to synthesize natural products which can inhibit pathogens but that also members of the human microbiome have this capacity. Staphylococcus lugdunensis living in the human nose was shown to produce lugdunin, a peptide antibiotic inhibiting the growth of S. aureus. Section B was dealing with all aspects of the interaction of bacteria with host cell via the cell envelope. Stud- ies on new structural data of adhesins, on the assembly of β-barrel proteins in the bacterial cell envelope and in mitochondria, and the immune reaction of plants confronted with bacterial pathogen resulted in a better understanding how bacteria infect their hosts. Research on the bacterial cell wall also gains new importance because of the increasing threat caused by antibiotic-resistant pathogens. The bacterial cell wall is the preferred target for the most effective antibiotics. Research on their mode of action and the resistance mechanisms combined with work on cell wall synthesis provides information, which helps to find new and to improve established antibiotics. In this context, we could identify new resistance mechanisms against lipid II binders, and characterize essential processes in cell envelope synthesis that may constitute novel targets for new antibiotics. The activities of the CRC 766 resulted also in important structural developments: it initiated the foundation of the Interfaculty Institute for Microbiology and Infection Medicine (IMIT) of the University. The successful re- search in the CRC 766 was decisive for the selection of Tübingen as a central partner site of the German Center for Infection Research (DZIF). These achievements finally made it possible to succeed with the pro- posal on “Controlling Microbes to fight Infection” initiative in the excellence competition.

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