Targeting the Transcriptional Repressor LexA to Overcome Bacterial Resistance A Strategy Based on Drug Repurposing and Lead Optimization

Antimicrobial resistance is one of the most pressing threats to global health. A viable strategy to counteract resistant strains is the identification of microbial targets disrupting bacterial adaptation and survival. Among these, the SOS response plays a crucial role, as it promotes DNA repair, mutagenesis, filamentation, and biofilm formation. The transcriptional repressor LexA is a key player of this system and represents a promising target for novel antibacterial strategies. In our studies, we pursue the development of LexA inhibitors through a dual approach combining drug repurposing of FDA-approved benzoxaboroles and chemical optimization guided by structural insight. This would retard the emergence of resistance, thus facilitating the reintroduction of obsolete antibiotics.