Physiological and Developmental Role of Bacterial Ser/Thr Kinases

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Project Summary Bacteria employ signaling systems to sense and respond to their environment. This allows them to adjust their cellular physiology and collective behavior in response to environmental cues. One subset of these systems are the Hanks-type serine/threonine kinases and phosphatases. These signaling systems have been shown to be critical, and even often essential, for bacterial physiology, including cell growth and division, antibiotic tolerance and resistance, sporulation and germination, virulence, and biofilm formation. To accomplish this, these systems can regulate cellular function through direct post-translational modification of enzymes, or control transcription by adding an additional layer of regulation to the activity of transcription factors from other pathways. As a result, the activity of Hanks-type Ser/Thr signaling systems remains poorly understood, particularly at the single-cell level, where these systems are known to regulate the appearance of rare cells with extreme phenotypes such as increased antibiotic resistance and bacterial virulence. The long-term goal of my laboratory is to explore how these signaling systems regulate population and single-cell-level phenotypes and thereby to understand their contribution to human health and disease. To do so, we will 1) perform a mechanistic and quantitative study of conserved bacterial Hanks-type Ser/Thr kinase-phosphatase systems, focused on understanding how their regulatory architecture enables the generation of rare cells in bacterial populations with extreme phenotypes, 2) determine the role of these signaling systems in developmental transitions such as competence, biofilm formation, and sporulation. Initially we will focus on these systems in the model organism Bacillus subtilis, with the long-term goal to uncover the conserved features that can be generalized to other, less genetically tractable, and clinically important bacteria.