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

近年来，不同微生物的多药耐药发展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，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，但它无意中选择了耐药微生物生存和繁殖，从而造成了一个重大的长期问题，并且它们的耐药基因可以进一步遗传和水平传递给其他人，从而彻底改变人类肠道中的微生物群。一个主要后果是新抗生素的临床使用寿命迅速缩短，给制药公司收回开发成本造成相当大的困难，从而削弱了新药开发的动力。在正在探索的所有抗菌素选择中，疫苗接种是预防和治疗脑膜炎、伤寒、霍乱等主要细菌感染的一种经证实有效的方法；其他最近的策略包括使用化疗药物靶向细菌毒力因子，细菌产生的生物分子能够增强其致病性。这些分子的例子是那些涉及细菌定植，运动，群体感应等。碳水化合物在上述所有过程中起着至关重要的作用；因此，细菌表面的碳水化合物构成了一类重要的毒力因子。其中一些根据细菌菌株具有非常独特的结构特征，使其成为有价值的疫苗靶点。Ling小组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的最新进展，以促进对感染中涉及的关键生物过程的理解，并开发预防和治疗疾病的有效工具。在目前的发现基金提案中，我们的目标是开发一种特殊类型的碳水化合物的有效合成，这种碳水化合物被称为非音速酸，它在细菌世界中广泛表达。它们属于一个独特的9碳糖家族，它们在运动中起着重要作用。该资助将包括三个目标：1)开发有效的化学和化学酶方法，以获得假胺酸及其衍生物以及其他相关的非音速酸；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，培养针对不同菌株的碳水化合物特异性抗体。拟议的研究将通过提高一般人口的健康水平和促进医药发展使加拿大受益。

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.