Development of therapeutic agents blocking SOS activation

Multi-Drug Resistant Bacteria represent a global emergency, limiting the effective treatment of bacterial infections. The situation is even more dramatic if we consider the limited number of new antimicrobial agents currently in clinical phase. SOS response, orchestrated and triggered by LexA-RecA(ssDNA-bound) interaction, has been recently validated as a key target for combating the evolution of antibiotic resistance. Blocking and/or modulation of RecA/LexA pathway have a direct effect on the expression of genes involved in SOS response and thus on the development of intrinsic resistance and acquisition of genes of resistance. The project, based on a multidisciplinary approach, focuses on the development of therapeutic agents blocking SOS activation, through the inhibition of LexA self-cleavage and/or interference with RecA/LexA interactions. Most promising molecules we are currently testing belongs to both boronic acids derivatives, identified in silico, and natural-compounds derived macrocycles. Furthermore, encouraging results have been obtained very recently in the development and screening of a nanobodies library targeting LexA-RecA complex. This option will be adopted both to rigidify the activated SOS-machinery for single particle cryo-EM studies, as well as a probe to investigate the minimal peptide scaffold able to block LexA active site. Such results will pave the way for peptide-based macrocycles building and optimization.