Integrating lipid biosynthesis with bacterial cell cycle progression

描述(申请人提供)：新月形杆菌是一种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。游动的丛生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，游动细胞排出它们的极鞭毛，并在以前鞭毛占据的同一极上建造一根柄(末端有粘合剂；用于附着在接近营养物的表面上)。有柄细胞能够进行DNA复制和细胞分裂。在细胞分裂过程中，鞭毛被放置在与茎相对的极处。铜绿假单胞菌预定的细胞周期由振荡的主调节器控制，这些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，鞭毛只有在需要时才被合成(恰好在细胞分裂之前)，并被放置在与茎相反的极处。同样，新的茎只在之前被鞭毛占据的杆子上合成。这项研究提案将使用药理学、遗传学和分子方法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调控机制，才能推动新型抗菌化合物的开发。脂肪生物合成是细胞存活所必需的，细菌脂肪酸合成酶被认为是抗生素的靶标。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。以前对细菌脂代谢的研究大多集中在大肠杆菌，一种伽马蛋白细菌。相比之下，硫杆菌作为一种α-蛋白细菌，与布鲁氏菌和立克次体等人类病原菌关系密切。因此，这项拟议的研究与公共卫生有关。 与公共健康相关：脂肪，也被称为脂类或脂肪酸，在从细菌到人类的所有细胞中都扮演着重要的角色。脂类形成膜，将细胞与环境隔开。这项研究计划旨在阐明脂类在细菌细胞分裂中的作用。通过识别对细胞分裂至关重要的细菌特有的脂酶(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.