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

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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.