Local and global regulation of bacterial growth

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To impact human health, bacteria must reproduce through successive rounds of growth and cell division. Moreover, bacteria must be able to adapt their growth to changing environmental conditions, including changes in nutrient availability or the presence of antibiotics, to ensure survival. Research in my laboratory focuses on two unanswered questions central to bacterial growth and adaptation. In the first, we ask how do bacterial cells locally regulate growth to achieve cell division? To address this question, we will build on our recent work demonstrating that the conserved, polymerizing GTPase FtsZ is a dynamic regulator of cell wall synthesis and remodeling during cell division. This idea represents a paradigm shift in defining FtsZ as an active regulator, rather than passive scaffold, for cell wall metabolism. We will leverage our expertise in bacterial genetics, imaging, biochemistry, and in vitro reconstitution to map the players and mechanisms in two signaling pathways from FtsZ to cell wall metabolism we identified in our model organism, Caulobacter crescentus. Given the urgent need for new antibiotics and proven efficacy of the cell wall as an antibacterial target, a complete understanding of the mechanisms and regulation of cell wall metabolism is a critical goal. In our second question, we ask how do bacteria adapt to changing nutrient availability and other stresses? We recently described the role of a conserved transcriptional regulator called CdnL in regulating metabolism, specifically in upregulating biosynthetic pathways, in Caulobacter. In addition, we have observed that CdnL is cleared from the cell during nutrient limitation in a manner dependent on the signaling alarmone ppGpp, suggesting a mechanism by which cells may downregulate transcription of proliferative pathways when nutrients are scarce. We will use a combination of genetic, genomic, and biochemical approaches to determine the contributions of CdnL inactivation and ppGpp to reprogramming transcription to ensure bacterial survival during nutrient limitation and other stresses. As both CdnL and ppGpp are implicated in adaptation to a variety of stresses in diverse bacteria, this work will inform our understanding stress and antibiotic resistance mechanisms in important bacterial pathogens.