IDENTIFICATION OF MOLECULES THAT INHIBITS c-di-GMP SYNTHESIS TO TARGET BIOFILM FORMATION

Bacteria are able to organize in organized communities named biofilms, difficult to eradicate, highly resistant to antimicrobials and to the host immune system. The scientific challenge is thus to find new therapeutic options that specifically target bacteria growing in biofilms. Cyclic di-GMP (c-di-GMP) is a widely conserved second-messenger and has a central role in modulation of several cellular processes, including the switch between planktonic and biofilm-related lifestyle. As this signalling system is found only in bacteria, targeting c-di-GMP metabolism represents thus an attractive strategy for the development of antibiofilm drugs. C-di-GMP levels are modulated by the opposite activity of diguanylate cyclase (DGCs), which catalyze its synthesis and phosphodiesterases (PDEs), which hydrolyze it. In order to provide a novel tool in treating drug-resistant bacterial infections, we are testing several compounds that target selectively c-di-GMP synthesis in vitro. We undertook two parallel and multidisciplinary approaches targeting active site by in silico screening of a small molecule database using known structure of DGC (PleD from C. crescents) and targeting inhibitory site by chemical synthesis of c-di-GMP analogues. Our results identify, by each approach, at least 2 compounds able to significatively decrease DGC activity. This promising results pave the way to test more compounds both in vitro end in vivo in human pathogens.