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Integrating lipid biosynthesis with bacterial cell cycle progression

将脂质生物合成与细菌细胞周期进程相结合

基本信息

批准号：
7667987
负责人：
Sean Murray
金额：
$ 14.3万
依托单位：
CALIFORNIA STATE UNIVERSITY NORTHRIDGE
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-08-05 至 2011-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7667987
关键词：
Acetates Address Adhesives Advanced Development Affect Alphaproteobacteria Animal Model Antibiotics Bacteria Binding Brucella C-terminal Caulobacter Caulobacter crescentus Cell Cycle Cell Cycle Progression Cell Cycle Proteins Cell Polarity Cell Survival Cell division Cells Cerulenin DNA biosynthesis Data Defect Environment Enzymes Escherichia coli Esters Fatty Acids Fatty acid glycerol esters Flagella Fluorescence Microscopy Gammaproteobacteria Gas Chromatography Genes Genetic Human Link Lipids Location Maps Mastigophora Measures Membrane Membrane Lipids Microbe Molecular Molecular Genetics Monitor Mutation N-terminal Normal Cell Nutrient Phenotype Play Process Protein Overexpression Proteins Public Health Recombinant Proteins Research Proposals Resistance Rickettsia Role Signal Transduction Site Surface Swelling Time Western Blotting antimicrobial fatty acid biosynthesis genetic regulatory protein inhibitor/antagonist interest knockout gene lipid biosynthesis lipid metabolism mutant overexpression pathogenic bacteria prevent promoter protein B public health relevance research study stoichiometry synthetic enzyme vector

项目摘要

DESCRIPTION (provided by applicant): The dimorphic bacterium Caulobacter crescentus is a model organism for studying the bacterial cell cycle. Its asymmetric cell division results in one swarmer and one stalked cell progeny. Motile swarmer cells can not undergo DNA replication until they differentiate into stationary stalked cells. If sufficient nutrients are available, swarmer cells eject their polar flagellum and build a stalk (with adhesive at its end; for attaching to a surface near nutrients) at the same pole formerly occupied by the flagellum. Stalked cells are competent for DNA replication and cell division. During cell division, a flagellum is placed at the pole opposite that of the stalk. Caulobacter's obligate cell cycle is controlled by oscillating master regulators that control different genetic modules in space and time. As a result of this carefully orchestrated process, a flagellum is synthesized only when needed (just prior to cell division) and is placed at the pole opposite that of the stalk. Likewise, a new stalk is synthesized only at the pole previously occupied by a flagellum. This research proposal will address the roles of lipid biosynthesis in this process, using pharmacological, genetic, and molecular approaches. Only by further elucidating the control mechanisms of bacterial cell division can we advance the development of new antimicrobial compounds. Lipid biosynthesisis essential for cell viability and bacterial fatty acid synthetic enzymes have been suggested as antibiotic targets. In fact, compounds specific to bacterial fatty acid biosynthetic compounds have been generated. Most previous studies on bacterial lipid metabolism have focused on E. coli, a gamma-proteobacteria. Caulobacter in contrast, as an alpha-proteobacteria, is closely related to human pathogenic bacteria, such as Brucella and Rickettsia. Thus, the proposed study is relevant to public health. Relevance to Public Health: Fat, also known as lipids or fatty acids play important roles in all cells, from bacteria to humans. Lipids form membranes that separate cells from their environment. This research proposal aims to elucidate the roles of lipids in bacterial cell division. By identifying lipid enzymes important for cell division that are unique to bacteria (i.e. not present in humans), we can identify new antibiotic targets. If we can prevent the synthesis of these lipids, we can prevent bacteria from dividing.

描述（由申请人提供）：二态性细菌新月柄杆菌是用于研究细菌细胞周期的模型生物。它的不对称细胞分裂产生了一个群细胞和一个有柄细胞后代。运动的群细胞在分化成静止的有柄细胞之前不能进行DNA复制。如果有足够的营养物质，集群细胞会弹出它们的极鞭毛，并在以前被鞭毛占据的同一极上形成一根茎（末端有粘合剂；用于附着在靠近营养物质的表面）。有柄细胞能够进行DNA复制和细胞分裂。在细胞分裂期间，鞭毛位于与茎相对的极处。柄杆菌的专性细胞周期由振荡主调节因子控制，这些主调节因子在空间和时间上控制不同的遗传模块。由于这个精心策划的过程，只有在需要时（就在细胞分裂之前）才合成鞭毛，并将其放置在与茎相对的极点上。同样，新的茎仅在先前被鞭毛占据的极处合成。该研究计划将利用药理学、遗传和分子方法探讨脂质生物合成在此过程中的作用。只有进一步阐明细菌细胞分裂的控制机制，才能推进新型抗菌化合物的开发。脂质生物合成对于细胞活力至关重要，细菌脂肪酸合成酶已被建议作为抗生素靶点。事实上，已经产生了细菌脂肪酸生物合成化合物特有的化合物。之前大多数关于细菌脂质代谢的研究都集中在大肠杆菌（一种γ-变形菌）上。相比之下，柄杆菌作为一种α-变形菌，与人类致病菌密切相关，例如布鲁氏菌和立克次氏体。因此，拟议的研究与公共卫生相关。与公共健康的相关性：脂肪，也称为脂质或脂肪酸，在从细菌到人类的所有细胞中发挥着重要作用。脂质形成将细胞与其环境分开的膜。该研究计划旨在阐明脂质在细菌细胞分裂中的作用。通过识别细菌特有的对细胞分裂很重要的脂质酶（即人类中不存在的酶），我们可以识别新的抗生素靶点。如果我们能够阻止这些脂质的合成，我们就可以阻止细菌分裂。