Our research takes part of worldwide efforts to discover new antibiotics  against tuberculosis, which is actually a leading cause of infectious disease mortality. More precisely, our approach aims at interfering with the biosynthesis of iron III chelators specific to the Koch bacillus, the mycobactins 1. As shown below, the start of this biosynthesis involves a key-adenylation domain, called MbtA, in charge, not only of the activation of salicylic acid as an adenosylmonophosphate derivative 2, but also of the anchoring of the salicyl moiety onto  a megaenzyme.¹


    In collaboration with Pr. Marahiel’s team in Marburg, in charge of the enzymatic tests, our work deals with the preparation of hydrolytically stable analogs of the intermediate 2. It has already been highlighted, simultaneously with Quadri et al.,² by the synthesis of sulfamate 4,³ the first inhibitor of mycobactin biosynthesis. We have prepared since the indoyl derivative 3, which represents the first phosphorylated analog of  2 to possess a good inhibitory activity on MbtA.⁴ We presently work on the preparation of other hetero-aryls in the sulfamate and phosphonamidate series.

1.  L. E. N. Quadri, J. Sello, T. A. Keating, P. H. Weinreb, C. T. Walsh Chem. Biol. 1998, 5, 631.
2.  J. A. Ferreras, J.-S. Ryu, F. Di Lello, D. S. Tan, L. E. N. Quadri Nature Chem. Biol. 2005, 1, 29.
3.  M. Miethke, P. Bisseret, C. L. Beckering, D. Vignard, J. Eustache, M. A. Marahiel FEBS J. 2006, 273, 409.
4.  P. Bisseret, S. Thielges, S. Bourg, M. Miethke, M. A. Marahiel, J. Eustache Tetrahedron Lett. 2007, 48, 6080.
 

Buruli ulcer program (Project manager : Dr. N. Blanchard)

   Being present in many natural products and bioactive compounds (antibiotics for exemple), polysaccharides are one of the most important classes of biomolecules. Besides the well known oligo/polysaccharides made of classical sugars such as glucose, galactose or mannose, some uncommon interesting oligosaccharides contain unusual sugar units. For example, several antibiotics and antitumor agents feature polydeoxy-saccharide moieties.

   In the last five years polyunsaturated oligosaccharides have been proposed as versatile synthetic intermediates in the preparation¹ of oligosaccharides, including polydeoxysaccharides. In such intermediates, the olefinic double bonds can be functionalized in various ways. Unfortunately, the few iterative methods which have been reported so far do not provide the degree of flexibility required for example for SAR studies in a medicinal-chemistry program. For these reasons, we are studying a novel, non iterative approach to polyunsaturated polysaccharides via a ring-rearrangement metathesis (RRM) key step.²
   
    We recently reported the synthesis of di- and trisaccharides using this new methodology³ (scheme 1).