Synthetic Studies of Bacterial Glycans

细菌表面覆盖着碳水化合物分子(多糖)，这些分子在细菌的生命周期中发挥着关键作用。这些多糖通常是生命所必需的，有助于保护这些有机体免受环境的影响，通常会调节受感染宿主的免疫系统。这些碳水化合物的组装途径是潜在的药物作用靶点，基于这些结构的疫苗是有效的预防感染的保护剂。化学合成细菌多糖用于基础化学和生化研究的能力是实现这些更具医学意义的目标的必要前提。几年来，我的团队一直在研究分枝杆菌的多糖的合成、构象和生物化学，包括引起结核病的微生物结核分枝杆菌。最近，我们开始了一个关于空肠弯曲菌多聚糖的合成项目，这是食物中毒的常见原因。我们建议在此继续我们的细菌多糖合成计划，重点放在三个方面。我们将：1)扩大我们对弯曲杆菌多糖的合成工作；2)合成结构明确的多糖作为脂多糖生物合成的探针；3)合成缓根糖，一种存在于根瘤菌中的双环单糖及其相关衍生物。所有这些项目中的一个关键组成部分是需要开发新的合成途径和方法，以解决目标的不寻常结构或分子的大小。尤其重要的是，到目前为止，这些目标几乎没有受到合成化学家的关注。我们的工作将是这一领域的第一项工作，因此将对该领域的其他工作产生影响，就像我们之前对分枝杆菌多糖合成的研究一样。该计划将在一个致力于培养具有知识、企业家精神和知识产权的独立科学家的计划的支持下，提供最先进的复杂多糖合成方面的培训。这里提出的合成工作将导致合作者在研究中使用分子，以更详细地了解细菌多聚糖的组装和生物学作用。

The surfaces of bacteria are coated with carbohydrate-containing molecules (glycans) that play critical roles in their life cycles. These glycans are usually essential for life and help protect these organisms from their environment, often modulating the immune system of infected hosts. The pathways by which these carbohy- drates are assembled are potential targets for drug action, and vaccines based on these structures are effective protectants against infection. The ability to chemically synthesize bacterial glycans for use in fundamental chemical and biochemical studies is a necessary prerequisite to achieving these more medically relevant goals. My group has, for several years, studied the synthesis, conformation and biochemistry of glycans from mycobacteria, including Mycobacterium tuberculosis, the organism that causes tuberculosis. Recently, we began a synthetic program on glycans from Campylobacter jejuni, a common cause of food poisoning. We propose here to continue our program on the synthesis of bacterial glycans by focusing on three areas. We will: 1) Expand our synthetic work on campylobacter glycans; 2) Synthesize structurally defined polysaccharides as probes for lipopolysaccharide biosynthesis; 3) Synthesize bradyrhizose, a bicyclic monosaccharide found in rhizobia, and related derivatives. A critical component in all of these projects is the need to develop new synthetic approaches and methodology to address either the unusual structure of the targets or the size of the molecules. Of particular significance, the targets have received little attention from synthetic chemists to date. Our work will be the first in this area and will thus be influential to others working in the field, much like our previous studies of mycobacterial glycan synthesis. This program will provide state-of-the-art training in complex glycan synthesis supported by a program dedicated to the development of independent scientists with a knowledge entrepreneurship and intellectual property. The synthetic work proposed here will lead to molecules for use in studies by collaborators directed at understanding, in greater detail, the assembly and biological role of bacterial glycans.