RésuméThe emergence of antibiotic resistance urges the scientific community to develop new therapeutic approaches. In the LPS structure, heptose is the first sugar that connects to Kdo2-lipid A. Its absence results in bacteria displaying a deep-rough phenotype that is characterized by a reduced protein content in outer membrane, a reduced motility, an increased sensitivity towards detergents or hydrophobic antibiotics and an enhanced susceptibility to phagocytosis by macrophages. Thus, the inhibition of heptose biosynthesis represents a promising strategy for the development of anti-virulence agents. Until now there were no reported inhibitors of GmhB and HldET, two key enzymes involved in the heptose biosynthesis. The corresponding substrates are D-glycero-D-manno-heptose 1β,7-bisphosphate (HBP) and D-glycero-D-manno-heptose 1-phosphate (H1P), respectively. When we started our study, there was no chemical synthesis of HBP. Interestingly, HBP was recently found to induce a TIFA-dependent inflammation mode, which was absolutely unprecedented for such bacterial metabolites.
Based on these two biological questions, we mainly focused on the synthesis of natural products HBP and H1P, as well as their phosphonate analogues. Starting with the construction of the D-glycero-heptose scaffolds in 9 steps, HBP and H1P were synthesized via an unusual Mitsunobu type double and β-selective phosphorylation. Then, seven phosphonates (including fluorinated ones) analogues of HBP and H1P were designed and synthesized on the basis of the central D-glycero-heptose scaffolds. Finally, in order to identify the natural receptor of HBP in human cells, a biotinylated probe was designed and synthesized from an advanced H1P precursor. All these analogues have been tested on inflammatory cells, and three analogues could induce a TIFA-dependent inflammatory response. In addition, all these analogues will be tested their inhibition of GmhB and HldET.
|la date de réponse||24 oct. 2019|
|Sponsors||China Scholarship Council|
|Superviseur||Stephane VINCENT (Promoteur), Johan Wouters (Président), STEVE LANNERS (Jury), Steven BALLET (Jury) & Christophe Biot (Jury)|