Optimizing growth rate, biomass and product formation of Lactococcus lactis by a Systems Biology approach (08080)

We plan to use a synthetic biology approach to produce >200 mainly silent, i.e. non-expressed in common growth media, lantibiotics from various genetic sources. To search for novel silent lantibiotic gene clusters we will mine all currently available bacterial genomes by means of state of the art bioinformatics programs including a novel bioinformatic tool called BAGEL. We will employ L. lactis that overproduces the nisin synthetase complex for lantibiotic synthesis and modification.. This has the great advantage that we can circumvent the need of including the corresponding biosynthetic, regulatory and immunity genes for each lantibiotic. After production of the novel natural lantibiotics, a thorough testing of the peptides against a library of target organisms will take place, including an initial screen for mode of action analysis. Our goal is to end up with at least 6 novel candidate lantibiotics that pass all tests and from which peptides will be selected for clinical trials.

Optimizing growth rate, biomass and product formation of Lactococcus lactis by a Systems Biology approach (project leaders Prof. Dr. Oscar Kuipers and Prof. Dr. Jan Kok)
L. lactis is the paradigm for industrially important microorganisms, Lactic Acid Bacteria in particular, which are of eminent importance in human and animal health and nutrition. Since cells have the option to use substrates for product formation, stress resistance or biomass formation, knowledge about the relationship between growth and product formation, under either optimal or stressed conditions, is of paramount importance in making the cells perform optimally from the perspective of industry. As virtually all processes of living cells are linked by intricate interactions, reaching the goals of this project requires (i), the study of the L. lactis cell in its entirety and (ii), integrative models to cope with the complexity of the system and the data. Hence, we need a Systems Biology approach to:
(i) Elucidate the relationship between growth rate and fermentative capacity of Lactococcus lactis
(ii) Determine how the relationship between growth and product formation is affected by long-term cultivation
(iii) Integrate the knowledge gained into a cellular model that can predict fermentative behaviour
The Systems Biology approach will be used to further the development of a predictive core model of the L. lactis cell, for which a preliminary draft is already available within the consortium. The model, using gPROMS modelling and simulation technology, will contain metabolic as well as gene regulatory and protein synthesis modules, and will be able to describe the trade-offs that a cell faces when coping with the environment.