FapR is a transcription factor that negatively controls the expression of several genes of the fatty acid and phospholipid biosynthesis in Bacillus subtilis. It is the first global regulator of lipid synthesis discovered in bacteria and is largely conserved in Gram positive organisms. A key intermediate in fatty acid biosynthesis, malonyl-CoA, acts as a negative effector of the transcriptional repressor FapR. We propose to use structural biology, genetic and biophysical approaches to study the molecular mechanisms by which malonyl-CoA modulates the DNA-binding activity of FapR.
The detailed understanding of this modulation mechanism will provide unique opportunities to learn how Gram-positive bacteria monitor the status of fatty acid biosynthesis and adjust the lipid synthesis accordingly. The major goal of this project is to carry out structural and biochemical studies of full-length FapR and its complexes with DNA and malonyl-CoA. Furthermore, as it has been recently shown that mutations disrupting the FapR -malonyl-CoA interaction resulted in a lethal phenotype in B. subtilis, we will also extend these studies to FapR from pathogenic bacteria such as B. anthracis, Staphylococcus aureus and Listeria monocytogenes.
This knowledge is expected to provide the bas is for the development of novel antibacterial compounds with potential therapeutic applications. The project is relevant to the specific objectives of the Marie Curie Incoming International Fellowships since a promising young researcher from Argentina will undertake research training in Europe and second, it will allow the development of mutually beneficial research cooperation between Europe and this third country. Moreover, the proposal includes a reintegration phase to assist the fellow to return to her country of origin and develop an independent research career.
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