The research plan described in this competitive renewal application continues successful investigations into the function of proteins involved in bacterial response and protection. For the most part, the proposed studies concentrate on the signal transduction pathway responsible for initiating sporulation in a variety of organisms. Self protection by endospore formation requires an enormous commitment of energy in order to change lifestyle and cell morphology, and is not a process bacteria enter into frivolously. Rather, they first enter a period of self-assessment referred to as the transition state, where processes required for both growth and survival are regulated simultaneously. During this period, the cell is managed by a novel class of proteins known as transition state regulators. A single transition state regulator is able to control a multitude of divergent cellular processes by binding to a set of seemingly unrelated promoter elements on a variety of genes, the transition state regulator AbrB will be characterized in terms of its structure, dynamics and DNA-binding propensities. Comparative studies with two homologous proteins, Abh and Spo0VT, will also be undertaken to determine the basis for the differing regulatory profiles of this class of proteins. Continued environmental hostility forces the cell to terminate the transition state and fully enter the sporulation cycle. A signaling cascade known as a multi-component phosphorelay is responsible for this process. At the core of this phosphorelay are four proteins - a kinase, a response regulator (SpoOF), a phosphotransferase (Spo0B) and a second response regulator (Spo0A), encompassing a pair of ubiquitous communication modules referred to as 'two-component systems'. Spo0A, when phosphorylated becomes a transcriptional regulator, forcing the transition state to end by repressing AbrB production. Studies here will focus on understanding the mechanisms of action of SpoOF and Spo0A. The system described is regarded as a paradigm for bacterial signal transduction systems required for environmental sensing, cell cycle control, cell-cell communication and virulence. From a health perspective, this latter point is particularly important. This system is known to be critically involved in the direct regulation of the expression of pathogens or the regulation of adaptive methods to protect against pathogens. Within the phosphorelay, the two component switches are vital for pathogenic development and have become a focal point for understanding and preventing infectious disease; they are also responsible for the development of antibiotic resistance in many bacteria and are potentially crucial in anti-infective design. Furthermore, the Spo0 phosphorelay and the transition state regulator AbrB have recently been found to be critical contributors in the development of inhalation anthrax infection. Our studies will correlate the function of the phosphorelay proteins with their structural and dynamic characteristics and will offer insight into both the onset of sporulation and also the action of transition-state regulators and response regulators in general. ? ?

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Molecular and Cellular Biophysics Study Section (BBCA)
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Flicker, Paula F
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North Carolina State University Raleigh
Schools of Earth Sciences/Natur
United States
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Draughn, G Logan; Milton, Morgan E; Feldmann, Erik A et al. (2018) The Structure of the Biofilm-controlling Response Regulator BfmR from Acinetobacter baumannii Reveals Details of Its DNA-binding Mechanism. J Mol Biol 430:806-821
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Stephens, Matthew D; Yodsanit, Nisakorn; Melander, Christian (2016) Evaluation of ethyl N-(2-phenethyl) carbamate analogues as biofilm inhibitors of methicillin resistant Staphylococcus aureus. Org Biomol Chem 14:6853-6
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Stephens, Matthew D; Yodsanit, Nisakorn; Melander, Christian (2016) Potentiation of the Fosmidomycin analogue FR 900098 with substituted 2-oxazolines against Francisella novicida. Medchemcomm 7:1952-1956

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