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.
