Integrating lipid biosynthesis with bacterial cell cycle progression

描述（申请人提供）：二态细菌新月形茎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跟踪细胞后代。运动的蜂群细胞在分化为静止的蜂群细胞之前不能进行DNA复制。如果有足够的营养物质，群生细胞会排出它们的极性鞭毛，并在原来由鞭毛占据的同一极点上形成茎（末端有粘着剂，用于附着在营养物质附近的表面）。被跟踪的细胞能够进行DNA复制和细胞分裂。在细胞分裂过程中，鞭毛位于与茎相对的两极。茎状杆菌的专性细胞周期由振荡的主调节器控制，该调节器在空间和时间上控制不同的遗传模块。由于这个精心安排的过程，鞭毛只在需要时才合成（就在细胞分裂之前），并被放置在与茎相反的极点上。同样，新的茎只在先前被鞭毛占据的极点合成。本研究计划将利用药理学、遗传学和分子方法探讨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，才能促进新的抗菌化合物的开发。细胞生存所必需的脂质生物合成和细菌脂肪酸合成酶已被认为是抗生素的靶点。事实上，已经产生了针对细菌脂肪酸的生物合成化合物。以前大多数关于细菌脂质代谢的研究都集中在大肠杆菌上，这是一种γ -变形菌。相比之下，Caulobacter作为一种α -变形菌，与人类致病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。

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.