Integrating lipid biosynthesis with bacterial cell cycle progression

描述（由申请方提供）：二型细菌新月柄杆菌是研究细菌细胞周期的模式生物。它的不对称细胞分裂导致一个蜂群和一个柄细胞后代。运动的群集细胞不能进行DNA复制，直到它们分化成静止的柄细胞。如果有足够的营养物质，蜂群细胞会弹出它们的极鞭毛，并在原来被鞭毛占据的同一极上建立一个柄（在其末端有粘合剂;用于附着在营养物质附近的表面）。茎细胞能够进行DNA复制和细胞分裂。在细胞分裂过程中，鞭毛被放置在与柄相对的极上。柄杆菌属的专性细胞周期由振荡的主调节因子控制，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，鞭毛只在需要时（就在细胞分裂之前）才合成，并放置在与柄相反的极点。同样地，一个新的柄仅在先前被鞭毛占据的极点处合成。这项研究计划将使用药理学，遗传学和分子方法来解决脂质生物合成在这一过程中的作用。只有进一步阐明细菌细胞分裂的控制机制，我们才能推进新的抗菌化合物的开发。脂质生物合成对细胞活力和细菌脂肪酸合成酶至关重要，已被认为是抗生素的目标。事实上，已经产生了对细菌脂肪酸生物合成化合物具有特异性的化合物。以往对细菌脂质代谢的研究主要集中在大肠杆菌。大肠杆菌，一种γ-变形菌。相比之下，柄杆菌作为α-变形菌，与人类病原菌如布鲁氏菌和立克次体密切相关。因此，拟议的研究与公共卫生有关。 与公共卫生的相关性：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重要作用。脂质形成膜，将细胞与环境隔开。这项研究计划旨在阐明脂质在细菌细胞分裂中的作用。通过识别对细菌特有的细胞分裂重要的脂质酶（即不存在于人类中），我们可以识别新的抗生素靶标。如果我们能阻止这些脂质的合成，我们就能阻止细菌分裂。

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.