Twenty Years of Mycobacterial Glycans: Furanosides and Beyond

[Image: see text] The cell surface (or cell wall) of bacteria is coated with carbohydrate (or glycan) structures that play a number of important roles. These include providing structural integrity, serving as a permeability barrier to extracellular compounds (e.g., drugs) and modulating the immune system of the host. Of interest to this Account is the cell wall structure of mycobacteria. There are a host of different mycobacterial species, some of which cause human disease. The most well-known is Mycobacterium tuberculosis, the causative agent of tuberculosis. The mycobacterial cell wall is characterized by the presence of unusual carbohydrate structures that fulfill the roles described above. However, in many cases, a molecular-level understanding of how mycobacterial cell wall glycans mediate these processes is lacking. Inspired by a seminar he heard as a postdoctoral fellow, the author began his independent research program with a focus on the chemical synthesis of mycobacterial glycans. The goals were not only to develop synthetic approaches to these unique structures but also to provide molecules that could be used to probe their biological function. Initial work addressed the preparation of fragments of two key polysaccharides, arabinogalactan and lipoarabinomannan, which contain large numbers of sugar residues in the furanose (five-membered) ring form. At the time these investigations began, there were few methods reported for the synthesis of oligosaccharides containing furanose rings. Thus, early in the program, a major area of interest was methodology development, particularly for the preparation of 1,2-cis-furanosides. To solve this challenge, a range of conformationally restricted donors have been developed, both in the author’s group and others, which provide 1,2-cis-furanosidic linkages with high stereoselectivity. These investigations were followed by application of the developed methods to the synthesis of a range of target molecules containing arabinofuranose and galactofuranose residues. These molecules have now found application in biochemical, immunological, and structural biology investigations, which have shed light on their biosynthesis and how these motifs are recognized by both the innate and adaptive immune systems. More recently, attention has been directed toward the synthesis of another class of immunologically active mycobacterial cell wall glycans, the extractable glycolipids. In this case, efforts have been primarily on phenolic glycolipids, and the compounds synthesized have been used to evaluate their ability to modulate cytokine release. Over the past 20 years, the use of chemical synthesis to provide increasingly complex glycan structures has provided significant benefit to the burgeoning field of mycobacterial glycobiology. Through the efforts of groups from around the globe, access to these compounds is now possible via relatively straightforward methods. As the pool of mycobacterial glycans continues to grow, so too will our understanding of their role in disease, which will undoubtedly lead to new strategies to prevent or treat mycobacterial infections.