Sulfoglycolipids and Related Analogues of Mycobacterium tuberculosis: Chemical Synthesis and Immunological Studies.

Mycobacterium tuberculosis (Mtb) causes tuberculosis as one major threat to human health, which has been deteriorated owing to the emerging multidrug resistance. Mtb contains a complex lipophilic cell wall structure that is important for bacterial persistence. Among the lipid components, sulfoglycolipids (SGLs), known to induce immune cell responses, are composed of a trehalose core attached with a conserved sulfate group and 1-4 fatty acyl chains in an asymmetric pattern. At least one of these acyl chains is polymethylated with 3-12 methyl branches. Although Mtb SGL can be isolated from bacterial culture, resulting SGL is still a homologous mixture, impeding accurate research studies. This up-to-date review covers the chemical synthesis and immunological studies of Mtb SGLs and structural analogues, with an emphasis on the development of new glycosylation methods and the asymmetric synthesis of polymethylated scaffolds. Both are critical to advance further research on biological functions of these complicated SGLs.

Tunable Strategy for the Asymmetric Synthesis of Sulfoglycolipids from Mycobacterium tuberculosis To Elucidate the Structure and Immunomodulatory Property Relationships.

We developed a versatile asymmetric strategy to synthesize different classes of sulfoglycolipids (SGLs) from Mycobacterium tuberculosis. The strategy features the use of asymmetrically protected trehaloses, which were acquired from the glycosylation of TMS α-glucosyl acceptors with benzylidene-protected thioglucosyl donors. The positions of the protecting groups at the donors and acceptors can be fine-tuned to obtain different protecting-group patterns, which is crucial for regioselective acylation and sulfation. In addition, a chemoenzymatic strategy was established to prepare the polymethylated fatty acid building blocks. The strategy employs inexpensive lipase as a desymmetrization agent in the preparation of the starting substrate and readily available chiral oxazolidinone as a chirality-controlling agent in the construction of the polymethylated fatty acids. A subsequent investigation on the immunomodulatory properties of each class of SGLs showed how the structures of SGLs impact the host innate immunity response.