Synthesis of Glycolipid Library Reminiscent of Mycobacterial Cell Wall Motif A and its Significance by Microscopy

Abstract

The cell wall of Mycobacterium tuberculosis is a complex structure composed of lipids, glycolipids, polysaccharides, and proteins. Key components include peptidoglycans (PG), lipoarabinomannan (LAM), and mycolyl arabinogalactan (mAG). Mycolic acid is covalently linked to arabinogalactan (AG) through ester bonds, creating a thick waxy layer on the bacterial surface that acts as a protective barrier against environmental threats and hinders the penetration of antibiotics. The terminal portion of arabinogalactan is motif A, a pentasaccharide characterized by two β-1,2 linkages and one each of α-1,5 and α-1,3 linkages. The C5 position of motif A is esterified with mycolic acid, further enriched by unusual cyclopropane. This study elaborates on the synthesis of a diverse array of MTb cell wall glycolipids inspired by motif A by employing silver-assisted gold-catalyzed glycosidations. Further, we explored their self-assembly behavior using microscopy. This collection of glycolipids includes variations with α or β-(1→2, 3, or 5) Araf linkages in di-, tri-, tetra-, and penta-arabinofuranosides, esterified with saturated, doubly unsaturated, or cyclopropanated long-chain fatty acids. The TEM analysis of the resulting self-assemblies revealed that subtle modifications in the anomeric linkages, length of the glycan, and the presence or absence of cyclopropanes impacted the morphology of the self-assembled structures.