Bacterial Wall Component Made

BY SYNTHESIZING a key oligosaccharide that tuberculosis bacteria include in their cell walls, a Canadian research team has taken a major step toward understanding how these microbes biosynthesize crucial parts of their anatomy.

The component, an arabinan domain, is among the largest oligosaccharides ever made chemically. The work could aid the design of TB drugs.

Arabinan domains help form the cell wall of the tuberculosis bacterium Mycobacterium tuberculosis and other mycobacteria. But the way these structures are biosynthesized is not well understood.

One hurdle has been the limited availability of arabinan oligosaccharides. Todd L. Lowary and coworkers at the Alberta Ingenuity Centre for Carbohydrate Science at the University of Alberta, Edmonton, have now ameliorated this problem by creating a 22-unit arabinan domain and an 18-unit putative precursor in the laboratory (J. Am. Chem. Soc., DOI: 10.1021/ja072892+).

"This is a great paper—a masterpiece of modern oligosaccharide synthesis," says professor David Crich of Wayne State University, Detroit, who specializes in such syntheses. The arabinan domain is a synthetic challenge "not only because of its size but because of the inclusion of the very difficult β-arabinofuranosides," Crich says. All 22 arabinan sugars are D-arabinofuranose residues, and four of these are β-arabinofuranosides, β-linked sugars that are hard to introduce in a stereocontrolled manner.

Other groups—such as those led by Peter Seeberger of the Swiss Federal Institute of Technology, Zurich, and Bert Fraser-Reid of the Natural Products & Glycotechnology Research Institute, Pittsboro, N.C.—have synthesized large fragments of lipoarabinomannan domains, mycobacterial cell-wall structures similar to arabinan domains. But those structures did not contain the synthetically challenging β-arabinofuranosides. The new study should clarify the biosynthesis of both lipoarabinomannan and arabinan oligosaccharides, as both types of domains are believed to share the same 18-unit biosynthetic precursor.

Lowary and coworkers accomplished the arabinan synthesis by preparing several oligoarabinofuranose building blocks and combining them, an approach called convergent synthesis. They added the four β-arabinofuranosides to the structure by using a method devised initially by Geert-Jan Boons and coworkers of the Complex Carbohydrate Research Center at the University of Georgia, Athens (J. Am. Chem. Soc. 2006, 128, 11948). The arabinan domain and precursor were each prepared from the building blocks in only six steps—a modest number for the synthesis of a complex oligosaccharide.

The block synthesis "greatly improves efficiency and allows for a modular construction and the ready access to analogs," Crich says. "The remarkable thing is the efficiency with which large pieces are joined together. This is truly a wonderful piece of work that will make available significant amounts of homogeneous samples of a biologically important target."

The arabinan biosynthetic pathway is indeed a promising drug target. The commercial anti-TB agent ethambutol is believed to act by blocking arabinan assembly, and the new study could aid discovery of novel anti-TB agents that work in a similar way.