Cyclic Dimeric GMP, a Novel Second Messenger in Bacteria: Molecular Mechanisms

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Cyclic dimeric guanosine monophosphate, c-di-GMP, is a key molecule involved in the lifestyle switch in bacteria, from single motile cells to surface-attached multicellular communities (biofilms). c-di-GMP controls this lifestyle switch by affecting bacterial motility, adhesion to surfaces, synthesis of extracellular matrix, stress resistance, and virulence. Gaining mechanistic insights into how c-di-GMP functions is of fundamental importance in bacteriology. Currently, a glaring gap exists between the large numbers of enzymes involved in c-di-GMP synthesis and hydrolysis (several dozen in most proteobacteria) and the small numbers (low single digits) of known c-di-GMP receptors, or effector proteins. This gap indicates that many c-di-GMP receptors have escaped identification. The long-term objective of this project is to identify new c-di-GMP receptors and uncover molecular mechanisms through which they operate in a model bacterium, Escherichia coli. In this project, new c-di-GMP receptors will be identified by genetic means as well as by the affinity-based capture. Because c-di-GMP, like other second messengers, works though conserved molecular mechanisms, it is expected that the insights derived from E. coli will inform strategies on controlling behavior of various bacterial species of medical, agricultural, environmental and biotechnological significance. The broader merit of this proposal lies in understanding the mechanisms that control bacterial behavior. This understanding is critical for designing pharmacological interventions that would allow us to manipulate bacteria in desirable ways. This project will offer interdisciplinary training opportunities in bioinformatics, bacterial genetics, protein-ligand biochemistry, and physiology to graduate and undergraduate students who will comprise the core research personnel. It will also provide research experiences to minority high school students enrolled in the Summer Research Apprenticeship Program. The project results will be presented at scientific meetings and published in research papers as well as in the articles for broader audiences.