The compound Araf22 is a key component of the tuberculosis bacterium’s protective cell wall. Copyright : 2011 Akihiro Ishiwata
A new strategy for synthesizing the kind of complex molecules
that certain bacteria use to build their protective cell walls
has been developed by Akihiro Ishiwata and Yukishige Ito from
the RIKEN Advanced Science Institute in Wako. The strategy
applies to Mycobacterium tuberculosis, the causative agent of
tuberculosis (TB), so it could lead to much-needed new
medicines to combat the spread of multi-drug-resistant strains
of the pathogen.
Disrupting the formation of the cell wall of M. tuberculosis is
already a proven strategy for treating TB, with several of the
current front-line drugs working in this way. However, the cell
wall skeleton is a complex, highly branched structure, and its
biosynthesis is not yet fully understood.
According to Ito, the compound he and Ishiwata made-a
sugar-based structure known as the arabinan motif (Araf22)
(Fig.1)-should be a useful biological probe, helping to unravel
cell wall biosynthesis. Perhaps more importantly, however, the
success of their strategy suggests that larger, more complex
cell wall components could be made in the same way.
Sugar-based compounds are notoriously difficult to make. Sugars
are bristling with reactive alcohol groups, so molecules made
from more than 20 sugar units pose a significant synthetic
challenge. Nevertheless, Ishiwata and Ito succeeded in clipping
together the branching chain of 22 sugar units needed to make
Their strategy involved synthesizing small sub-structures of
the mycobacterial cell wall skeleton and building from there.
To make the compound, they conceptually broke down Araf22’s
structure into several simpler fragments, chemically
synthesized those fragments, and then clipped them together to
make Araf22. This aspect of the strategy has been applied
before, but Ishiwata and Ito built the fragments such that they
clipped together at linear rather than branching points in
The researchers’ strategy makes the individual fragments more
difficult to build, but it makes the coupling process much more
efficient. Crucially, that means the strategy should work just
as well as a way to make even larger and more complex
components of the cell wall.
“One of the main points of this work is for us to show the way
to construct the more complex compounds,” says Ishiwata. “We
are now planning to synthesize more complex but structurally
reliable glycans of cell wall skeletons for biological
studies.” However, such compounds could even prove to be useful
drugs in themselves, if they are able to disrupt the cellular
machinery responsible for mycobacterial cell wall biosynthesis.
Synthetic Cellular Chemistry Laboratory, RIKEN Advanced Science
Link to paper ‘Synthesis of docosasaccharide arabinan motif of
mycobacterial cell wall’