Characterization of environmental stimuli and regulatory networks involved in the expression of the colibactin polyketide in E. coli

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Colibactin is a hybrid non-ribosomal peptide/polyketide genotoxin expressed in E. coli and different Enterobacteriaceae with the ability to cause DNA double strand breaks and thus to block the eukaryotic cell cycle. Due to this characteristics, colibactin can have important implications for human health. So far, studies about colibactin mainly focused on its effect on the host cells. The conditions under which this polyketide is expressed in E. coli are, however, only poorly understood. We postulate that colibactin expression is tightly controlled by environmental stimuli and the bacterial growth stage. Expression of the colibactin determinant is affected by different transcriptional and posttranscriptional regulatory circuits in response to host cell factors, the bacterial central metabolism and the bacterial growth stage or stress conditions. To test this hypothesis, we will:- characterize factors leading to strain-specific differences in colibactin expression- elucidate the regulation of ClbR expression and its role as a transcriptional activator of clb gene expression- analyze the control of clb gene expression by the 'carbon storage regulator' (Csr) system - investigate the putative correlation between stress, starvation, central metabolic pathways and colibactin expression.- study the integration of colibactin biosynthesis into global regulatory networks of E. coli. The comprehensive picture regarding the factors and conditions influencing the expression of colibactin will be very helpful to develop therapeutics against colibactin producing bacteria. Moreover, it will support colibactin overexpression and/or purification, which is a prerequisite for the functional and structural characterization of this interesting and still insufficiently studied compound.