Molecular Mechanisms of Bacterial Cell Wall Stability under c-di-AMP Regulation

All bacteria, including those of food production and foodborne illnesses, employ various signaling components to mediate normal physiology and pathogenesis. Among those, the small nucleotide c-di-AMP (hereafter denoted cdA) has recently emerged as a ubiquitous second messenger. CdA is present in most species of the gut microbiota, lactic acid bacteria, and prominent food-borne pathogens, such as Listeria monocytogenes, Staphylococcus aureus, and Clostridium sp. Whereas nucleotide second messengers are typically associated with certain physiological pathways, cdA has broad and global roles in various cellular processes, such as central metabolism, stress response, biofilm formation and virulence.The depletion of cdA severely weakens the bacterial cell wall. The L. monocytogenes dacA mutant exhibits substantial lysis in rich broth media and in the host cytosol, as well as increased sensitivity to cell wall antibiotics. The major goal of the proposal is to elucidate the molecular mechanisms by which cdA regulates bacterial cell wall stability. The objectives are: i) Regulation of cell wall stability through controlling osmolyte transport, ii) Regulation of cell wall biosynthesis