MECHANISMS OF POLYSIALIC ACID ASSEMBLY IN E COLI

尽管研究了半个多世纪和重大进展 在抗微生物治疗中， 细菌，包括脑膜炎球菌，肺炎球菌，嗜血杆菌， 流感病毒B型、大肠杆菌和B族链球菌， 仍然是一个重大的健康问题。 对预防和 对由这些细菌引起的疾病的控制已经得到了促进 这些疾病的高发病率和死亡率， 微生物，抗生素耐药菌株的出现， 以及地方病和流行病的威胁。 E.大肠杆菌是 新生儿脑膜炎最常见的原因与高 死亡率和严重的神经系统后遗症。 吉隆坡 多糖在结构上与聚唾液酸相同 神经细胞粘附分子NCAM上的部分，其可以 解释了E.大肠杆菌荚膜和 缺乏有效的疫苗，尽管大力开发疫苗 努力 事实上，目前尚不清楚针对Kl的疫苗是否 胶囊是理想的。 疾病的替代方法 控制将是旨在破坏细菌的治疗方法， 唾液酸代谢 这种方法需要详细的 关于聚唾液酸合成及其基础的信息 基因调控 我们目前对大肠杆菌kps基因簇的了解。杆菌Kl 是在一个复杂的水平，其中分子描述的 合成和调节机制可以在 统一方案。 结合强大的微生物遗传方法 分子和生物化学方法表明， 这是第一次完整地描述膜 多糖的合成，潜在的遗传调控， 易位是可能的。 这些信息将与 用于医疗和工业的其他胶囊生物合成系统 重要性 在这里，我们提出实验，以进一步定义聚合酶 负责聚唾液酸合成的复合物， 阐明环境的遗传机制 调节胶囊表达，并开始开始功能性 重组聚合物组装和易位因子。 这些新的方法是我们的直接和合乎逻辑的延续， 以前的研究推断出一个功能基因图的 聚唾液酸基因簇。

Despite research for more than half a century and major advances in antimicrobial therapy, diseases caused by encapsulated bacteria, including meningococci, pneumococci, Haemophilus, influenzae type B, Escherichia coli, and group B streptococci, remain a major health problem. Interest in the prevention and control of disease caused by these bacteria has been stimulated by the high morbidity and mortality of disease caused by these microorganisms, the emergence of antibiotic resistant strains, and the threat of endemic and epidemic disease. E. coli is the most common cause of neonatal meningitis associated with high mortality and serious neurological sequelae. The Kl polysaccharide is structurally identical to polysialic acid moieties on the neural cell adhesion molecule, NCAM, which may explain the weak immunogenicity of the E. coli capsule and the lack of effective vaccines, despite intensive vaccine development efforts. Indeed, it is not clear whether vaccines against the Kl capsule would be desireable. An alternative approach to disease control would be therapeutics aimed at disrupting bacterial sialic acid metabolism. This approach requires detailed information about polysialic acid synthesis and its underlying genetic regulation. Our current understanding of the kps gene cluster in E. coli Kl is at a level of sophistication wherein molecular descriptions of synthetic and regulatory mechanisms can be investigated in a unified program. Combining powerful microbial genetic approaches with molecular and biochemical methodologies suggests, for the first time, that a complete description of a membrane polysaccharide's synthesis, underlying genetic regulation, and translocation may be possible. This information will be relevant to other capsule biosynthetic systems of medical and industrial importance. Here, we propose experiments to further define the polymerase complex that is responsible for polysialic acid synthesis, to elucidate the genetic mechanisms underlying environmental regulation of capsule expression, and to begin a functional reconstitution of polymer assembly and translocation factors. These new approaches are a direct and logical continuance of our previous research to deduce a functional genetic map of the polysialic acid gene cluster.