Chemical Tools to Probe the Activation of Bacterial Signaling

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Bacteria can sense and respond to the world around them. For example, a microbe in a hostile environment activates mechanisms of defense. However, it is not well understood how bacteria are able to differentiate between the many chemical stimuli that they encounter and respond accordingly. Professors Carlson and Goodpaster of the University of Minnesota uses chemical synthesis and biochemical methods to gain an understanding of the response pathways that bacteria use and how their responses are customized to a variety of environmental conditions, such as high temperature, low nutrients, or the presence of chemical compounds, such as antibiotics. This knowledge ultimately enables us to control the behaviors of bacteria to our advantage, including for the production of biofuels or natural products that can be used as drugs. A collection of educational activities introduces students, especially girls from low socioeconomic groups and diverse backgrounds, to the roles that microbes play in our lives. These efforts include interactions with the same cohort of girls and young women over multiple years, encouraging them to see themselves as scientists in their future careers. This program also provides opportunities for graduate students to mentor and teach students starting from age six and generates materials that are broadly disseminated to enable others to teach young students about bacteria and their many functions on our lives, both bad and good. With this award, the Chemistry of Life Processes Program is funding Professors Carlson and Goodpaster at the University of Minnesota to study how microbes translate the complex environment in which they live into the actions required to survive and thrive. Essential to this capability are the two-component system (TCSs), which consist of a histidine kinase and response regulator protein pair. A single organism possesses tens to hundreds of individual TCSs, each reacting with high sensitivity and selectivity to one or a small number of chemical signals. Each chemical message is converted into a defined bacterial action, ranging from growth, motility, biosynthesis of natural products, and pathogenesis. Although numerous individual TCSs have been studied, current methodologies do not enable global assessment of the conditions under which many of them are induced, characterization of the relationship between TCS signal transduction and phenotypic results, or the regulation of response between multiple TCSs. A deeper understanding of TCS-mediated signaling is achieved by: 1) Synthesis and evaluation of molecules to develop an understanding of how to internalize phosphate-containing molecules into bacteria, and 2) Develop chemical proteomics methodologies to pair TCSs with their stimulating molecule(s) and to globally map HK activation by environmental stressors in live cells. The overarching goal is to define the suite of TCSs that are required for a generic stress response and those that are stimulus-specific. This information promotes a deeper understanding of how bacteria are able to utilize their relatively limited genome to orchestrate response to nearly limitless stimuli. This goal is aligned with one of the NSF 10 Big Ideas, Understanding the Rules of Life. A set of rules that predict an organism's observable characteristics and its phenotype, as it relates to the roles of the TCSs, is elucidated. These research goals are complemented with educational and outreach activities, focused on girls from low socioeconomic groups and diverse backgrounds, that introduce them to the roles that microbes play in our everyday lives.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.