c-di-GMP-based molecules as potent diguanylate cyclase (DGC) inhibitors

The emergence of antibiotic and multi-target resistant bacterial strains is a major life-treating health problem with high socio-economic costs in developed countries. Thus, innovative strategies to target antibiotic- resistant infections are urgently needed. In the establishment of chronic infections, one of the crucial steps is the transition of bacteria from the planktonic to the biofilm lifestyle.[1] The intracellular levels of the second messenger cyclic di-GMP (c-di-GMP) play a crucial role in this transition. Indeed, high intracellular c-di-GMP levels positively correlate with bacterial processes relevant for chronic virulence and biofilm formation. Since the pathways involved in c-di-GMP signaling are not present in mammalians, they represent attractive targets for the development of antibacterial drugs. The intracellular levels of c-di-GMP are regulated by the opposite activities of diguanylate cyclases (DGC), involved in c-di-GMP synthesis, and phosphodiesterases (PDE), involved in c-di-GMP degradation. Therefore the identification of compounds inhibiting the DGC activity would allow the development of new anti-biofilm drugs. Following a molecular simplification approach on the chemical structure of c-di-GMP, and a click chemistry methodology, an array of c-di-GMP-based compounds was designed, synthesized and tested against enzymes involved in c-di-GMP metabolism. Two of the novel compounds were able to significantly inhibit DGC activity, targeting the I-site of PleD from Caulobacter crescentus. References 1. Romling, U. & Balsalobre, C. Biofilm infections, their resilience to therapy and innovative treatment strategies. J. Intern. Med., 2012, 272, 541-561.