Total synthesis of membrane lipids from Mycobacterium tuberculosis

Every year, 1.5 million people die of  tuberculosis worldwide, the World Health Organization (WHO) states. Tuberculosis is caused by the bacterial pathogen Mycobacterium tuberculosis (Mtb). The (glyco)lipids from the cell wall of this pathogen exhibit immunological properties and hold potential as vaccine adjuvants. In his thesis, Zonghao Lin elaborates the structure determination and structure revision of di-O-acyl-trehalose (DAT2) and its methyl-branched acyl substituent (mycolipanolic acid), tri-O-acyl-trehalose (TAT), tetra-O-acyl-trehalose (TetraAT) and lysyl-diacylglycerol. 

Lin developed efficient chemical synthesis routes for the asymmetric total synthesis of their stereoisomers and analysed these using NMR, HPLC, GC, and mass spectrometry. Biological assays demonstrated that the natural stereoisomer of DAT2 markedly activates the macrophage receptor Mincle, highlighting its antigenicity and potential applications in serodiagnostics and vaccine adjuvants. Based on the structural correction of penta-O-acyl-trehalose (PAT) and the synthesized biosynthetic intermediates TAT and TetraAT, Lin confirms his hypothesis for the biosynthesis of PAT. Additionally, Lin presents attempts to synthesize N’-carboxymethyl lysyl diacylglycerol and a novel trehalose probe equipped with a geminal chloro-nitroso unit. These, though currently unsuccessful, indicate a need for further exploration. 

In conclusion, Lin has completed the total synthesis of DAT2, TAT, TetraAT and lysyl-diacylglycerol and their structural determination using chromatographic and spectroscopic analytic methods. Further research will be required for the synthesis of N’-carboxymethyl lysyl diacylglycerol and geminal chloro-nitroso trehalose and potential applications of the synthesized acylated trehaloses in vaccine adjuvant development.

Dissertation: https://hdl.handle.net/11370/de570323-1659-4691-b524-7ded2aa34d1b