报告题目：Synthetic and systems biology with Gram-positive bacteria with special emphasis on Streptomycetes: state-of-the-art and future perspectives

报 告 人：Prof. Jozef Anné

University of Leuven, Dep. Microbiology and Immunology,Belgium

报告时间：9月24日（星期三），14:00

报告地点：徐汇校区哲生馆1楼会议室

联 系 人：林双君 This e-mail address is being protected from spambots. You need JavaScript enabled to view it.

报告摘要：

From an economic point of view, high yield is essential for microbial production of (bio)chemicals and biopharmaceuticals. Optimizing pathway flux, reducing toxic intermediates, and balancing stress on the cell are the most important factors required to reach maximal yields. The event of synthetic and systems biology offers now unprecedented opportunities for rational understanding of cell complexity and allows the diversion and exploitation of their biochemical pathways and the introduction of new ones.

Streptomycetes and related bacteria produce most of the antibiotics used today to treat bacterial and fungal infections as well as anti-cancer drugs. In addition, certain industrially relevant proteins can only in Streptomyces efficiently be expressed. However, the growth characteristics of Streptomyces are often sub-optimal, exhibiting a long exponential phase, production of unwanted secondary metabolites, and reaching relatively low cell density in fermentations. With the onset of the “omics” era, it has become possible to study the physiology of these bacteria in unprecedented detail, thus opening new possibilities for rational engineering of Streptomyces toward platform hosts for sustainable production of valuable molecules. Such engineering, however, remains a challenging task due to a complexity of regulatory and metabolic networks linking growth, morphological differentiation and biosynthesis. This issue becomes especially important when genes for biosynthesis of an exogenous molecule (e.g. a secondary metabolite or a protein) are introduced and expressed. On the one hand removal of intrinsic metabolic and regulatory pathways known or suspected to interfere with production of heterologous target molecules can circumvent most of the problems with heterologous production.

Among the bacterial systems applied as platform for the production of biopharmaceuticals and industrial enzymes, Streptomyces is an attractive host, because several strains have a naturally high secretion capacity and low endogenous protease activity. It has been shown that several proteins are secreted to commercially acceptable levels using this host. On the other hand, many heterologous proteins, most often of eukaryotic origin, are poorly secreted by this host, indicating the need for its further optimization as production host. Bottlenecks can be located at different levels, ranging from transcription and translation of the heterologous gene to the secretion process and the secretome-metabolome interactions.

Combining genomic data, metabolic network modelling, metabolic flux analysis, metabolomic data and transcriptomic/proteomic data, a systems biology approach can be used to identify genes/proteins with key roles in protein secretion and their interrelationship with cell growth, secretion stress control and energy production/consumption. This information can then permit the targeted manipulation of specific genes or metabolic pathways for a better energy generation or directed energy consumption for either the cell mass production or for recombinant protein production and secretion. The efforts and strategies made in recent years, aimed at improving bacterial hosts for the production of recombinant proteins and new biopharmaceuticals will be reviewed. Particular attention will be given to Streptomyces.