The Development of Efficient Synthesis of Bacterial Nonulosonic Acids for immunological Studies

用于免疫学研究的细菌非努糖酸的高效合成研究进展

• 批准号: RGPIN-2018-04320
• 负责人: Ling, ChangChun
• 金额: $ 6.99万
• 依托单位: University of Calgary
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=747976
• 关键词: Development; Efficient; Synthesis; Bacterial; Nonulosonic

The development of multidrug resistance by different microorganisms has become a major global concern during recent years. The primary cause for this development can be tracked to our general antibacterial strategy which primarily relies on the use of chemotherapeutic agents to kill microorganisms or inhibit their growth. Unfortunately, most drugs used in clinics are non-selective which target both pathogenic and nonpathogenic microorganisms. Although such approach is generally effective, it creates a major long-term problem by unintentionally selecting drug-resistant microorganisms to survive and flourish, and their drug-resistant genes can be further passed on to others both hereditarily and horizontally, thus drastically altering the microflora in human intestines. A major consequence is the rapid shortening of the clinical lifetime of new antibiotics, creating considerable difficulties for pharmaceutical companies to recover development costs, which demotivates new drug development. Among all antimicrobial options being explored, vaccination is a proven effective method of prevention and treatment of key bacterial infections, such as meningitis, typhoid, cholera; other more recent strategies involve using chemotherapeutics to target bacterial virulence factors which are biomolecules produced by bacteria to enable and enhance their pathogenicity. Examples of such molecules are those involved in bacterial colonization, motility, quorum sensing etc. Carbohydrates play many crucial roles in all above processes; thus bacterial surface carbohydrates constitute an important class of virulence factors. Some of them have very unique structural features according to bacterial strains, making them valuable vaccine targets. The long term research objectives of the Ling group are to develop innovative synthetic chemistries and apply recent advances in carbohydrate chemistry and glycobiology to advance understanding of key biological processes involved in infections and develop effective tools for the prevention and treatment of diseases. In the current Discovery Grant proposal, we aim to develop efficient synthesis for a specific class of carbohydrates called nonulosonic acids, which are widely expressed in the bacterial world. They belong to a distinct family of 9-carbon sugars that have been recognized for their role in motility. The grant will consist of three aims: 1) develop efficient chemical and chemoenzymatic methodologies to obtain pseudaminic acid and derivatives as well as other related nonulosonic acids; 2) develop inhibitors for a key aldolase NeuB3 involved in the biosynthesis of Pse and analogs; 3) develop Pse-based conjugate vaccines to raise carbohydrate specific antibodies against different strains of bacteria. The proposed research will benefit Canada through advances in the health of the general population and pharmaceutical development.

近年来，不同微生物产生的多药耐药已成为全球关注的主要问题。这一发展的主要原因可以追溯到我们的一般抗菌策略，该策略主要依赖于使用化疗药物来杀死微生物或抑制它们的生长。不幸的是，临床上使用的大多数药物都是非选择性的，既针对致病微生物，也针对非致病微生物。虽然这种方法通常是有效的，但它造成了一个重大的长期问题，因为它无意中选择了耐药微生物来生存和繁衍，它们的耐药基因可以进一步遗传给其他人，无论是遗传还是水平，从而彻底改变了人类肠道的微生物区系。一个主要后果是新抗生素的临床寿命迅速缩短，给制药公司回收开发成本带来了相当大的困难，这打击了新药开发的积极性。在所有正在探索的抗菌素选择中，疫苗接种是被证明是预防和治疗关键细菌感染的有效方法，如脑膜炎、伤寒、霍乱；其他较新的策略包括使用化疗药物来靶向细菌毒力因子，这些毒力因子是细菌产生的生物分子，以使其能够致病并增强其致病性。这类分子的例子包括那些参与细菌定植、运动、群体感应等的分子。碳水化合物在上述过程中发挥着许多关键作用，因此细菌表面碳水化合物构成了一类重要的毒力因子。根据细菌菌株，它们中的一些具有非常独特的结构特征，使它们成为有价值的疫苗靶标。凌氏集团的长期研究目标是开发创新的合成化学，并应用碳水化合物化学和糖生物学方面的最新进展，以促进对感染所涉及的关键生物过程的了解，并开发有效的疾病预防和治疗工具。在目前的发现拨款提案中，我们的目标是开发一种名为非磺酸的特定碳水化合物的有效合成，这种碳水化合物在细菌世界中广泛表达。它们属于一个独特的9-碳糖家族，该家族因其在运动中的作用而被公认。这笔赠款将包括三个目标：1)开发有效的化学和化学酶方法，以获得伪氨基酸及其衍生物以及其他相关的非磺酸；2)开发参与PSE及其类似物生物合成的关键醛缩酶NeuB3的抑制剂；3)开发基于PSE的结合疫苗，以提高针对不同细菌株的碳水化合物特异性抗体。拟议的研究将通过在普通人群的健康和制药开发方面的进展而使加拿大受益。