Osmolarity-dependent control of cellular c-di-AMP levels and characterization of osmolyte transporters in Listeria monocytogenes

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Cyclic di-AMP is a signalling nucleotide that is produced by many Gram-positive bacteria, including the human pathogen Listeria monocytogenes. C-di-AMP is synthesized and degraded by specific diadenylate cyclases and phosphodiesterases, respectively. For L. monocytogenes and phylogenetically related bacteria it has been shown that c-di-AMP is essential for growth. Several targets have been identified in the past years that bind to c-di-AMP. As yet, none of the known targets of c-di-AMP is essential in the bacteria whose viability, however depends on the signalling nucleotide. Recently, we have shown that the CdaR protein negatively regulates the activity of the L. monocytogenes diadenylate cyclase CdaA. The observation that both proteins are located at the cell envelope, suggests that c-di-AMP metabolism is linked to cell wall homeostasis. Indeed, for many bacteria it has been reported that alterations of the cellular c-di-AMP levels affect integrity of the protective cell envelope. However, the role of c-di-AMP in cell wall metabolism is unknown. In the proposed project we want to identify the signals that are received by CdaR and how c-di-AMP produced by CdaA affects the integrity of the bacterial cell envelope. By applying genetic as well as biochemical approaches we aim to elucidate the interaction network of CdaA and its regulator CdaR. Moreover, we want to perform structural analyses to investigate the molecular details of the protein complexes. We also want to identify substances that inhibit CdaA because the essential diadenylate cyclase is an excellent target for novel antibiotics.