Bacterial stress responses mediated by c-di-AMP

About This Grant

Project Summary/Abstract Microorganisms employ diverse stress response systems to enable rapid and specific adaptations to environmental challenges such as antimicrobial stress, nutrient limitation, and osmotic pressure. The second messenger cyclic di-AMP (c-di-AMP) is produced by more than 11,000 bacterial and archaeal species, with its concentration fluctuating in response to these external stimuli and regulating carbon metabolism, osmotic homeostasis, cell wall synthesis, and DNA integrity. However, how bacteria translate external stimuli to c-di-AMP metabolism, as well as how c-di- AMP regulates bacterial physiology to alleviate cell stress remain poorly understood. Our recent findings reveal that elevated c-di-AMP production is associated with bacterial thymineless death regulation, a DNA damage-induced programmed cell death mechanism observed across all living cells. Additionally, we have identified c-di-AMP elevation as a conserved cell response to DNA damage across different Firmicutes, highlighting the importance of c-di-AMP as a global regulator for DNA integrity in bacteria. The long-term goal of our lab is to unravel previously undescribed bacterial stress response and adaptation mechanisms. The goal of this proposal is to investigate how early and late DNA damage signals, including DNA supercoil relaxation and DNA breaks, regulate c-di-AMP metabolism and how subsequent changes in c-di-AMP concentration influence nucleotide synthesis and salvage to facilitate DNA repair and inhibit cell death. By uncovering novel DNA integrity surveillance mechanisms, this foundational research will advance our understanding of bacterial stress responses and inform new strategies for developing antimicrobial targets.