LELAND STANFORD JUNIOR UNIVERSITY, THE
How do all the complex reactions composing a living cell work together to allow growth and accurate cell division? My work focuses on unraveling these mysteries in a simple bacterial cell. Key players in regulating bacterial cell growth are the histidine kinase enzymes, and one in particular?CckA?appears to be the lynchpin in controlling the Caulobacter crescentus cell cycle. A fundamental question is: how does the cell activate CckA at the appropriate time, triggering the complex genetic circuitry that culminates in cell division? I aim to identify factors that turn on CckA and pertinent partners that mediate this signal. Using a small-molecule inhibitor?a chemical that functions like a drug?directed against the CckA signaling pathway, I will selectively shut off CckA activation at the proper time in the Caulobacter cell cycle and study how cellular components respond. By identifying enzymes that function differently when CckA is inactive, I hope to uncover factors that trigger the cell cycle in space and time. I will find a small-molecule CckA inhibitor by testing >130,000 drug-like chemicals against Caulobacter engineered to report CckA inhibition. In addition, I seek to discover the genetic components that regulate CckA activity using a genome-wide screen for these signaling partners. Integrating discoveries from these pharmacological and genetic studies, this project will reveal the pertinent partners necessary to activate the cell cycle in Caulobacter, providing new insight into mechanisms that define how and when bacteria decide to divide. Our understanding of these fundamental aspects of bacterial physiology opens the door to potential new antibacterial targets.
PUBLIC HEALTH RELEVANCE: Development of novel antibiotics is essential to combat the emerging drug-resistant strains of bacteria that pose a serious threat to public health. Bacterial signaling pathways mediated by histidine kinases make ideal targets for the development of new antibiotics because they play a central?and often essential?role in controlling bacterial physiology. By developing a new way to find inhibitors targeting these histidine kinase signaling pathways and interrogating the role each signaling partner plays in conveying these signals, my work will facilitate systematic discovery of new pharmacological targets and development of histidine kinase inhibitors, paving the way to developing a new class of antibiotics.