A crucial but often overlooked aspect of cell biogenesis and survival is the need for precise coordination between the biosynthesis of its macromolecular constituents. In the case of bacterial cells, this means producing appropriate amounts of four classes of macromolecules : nucleic acids, proteins, lipids and the polysaccharides of the cell wall. The molecular basis of coordination is well known in some cases. In others it is still mysterious. In this project we propose to investigate how Gram-positive bacteria coordinate lipid and membrane synthesis with its other biosynthetic activities and in response to environmental conditions and the different events of the cell cycle. We plan to focus on two principal aspects: 1) the role of the enzyme PlsX in the coupling of fatty acid and phospholipids synthesis, and 2) the role of the signaling nucleotide ppGpp in the two-way coordination between lipid synthesis and cell growth. To achieve these goals we will apply modern fluorescence microscopy, microbial genetics and protein biochemistry to determine how PlsX associates with the cell membrane and how this affects its enzymatic activity and regulation. A similarly broad array of approaches will also be deployed to study how lipid starvation triggers the activation of the ppGpp synthetase RelA, and how this nucleotide helps cells stay alive in the absence of lipid synthesis Finally, we will set up assays and carry out small molecule screens for inhibitors of PlsX and RelA. Because proper control of lipid metabolism is essential for survival, the discoveries from this project should reveal potential novel targets for antibiotics. (AU)
Articles published in Agência FAPESP Newsletter about the research grant:
CAUZ, ANA C. G.;
CARRETERO, GUSTAVO P. B.;
SARAIVA, GREICE K. V.;
CUCCOVIA, IOLANDA M.;
GUEIROS-FILHO, FREDERICO J.
Violacein Targets the Cytoplasmic Membrane of Bacteria.
ACS INFECTIOUS DISEASES,
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