Synthetic RNA ligands as activators of type I toxin–antitoxin systems: a novel antimicrobial strategy targeting <i>Helicobacter pylori</i>

Targeting RNAs with synthetic small molecules represents a privileged avenue for the discovery of new therapeutic approaches and offers the possibility to identify original targets escaping the classical rules of druggability and resistance. In the context of multidrug resistance to antibiotics, an urgent need for new antimicrobial compounds is emerging; however both academia and industry are mostly working on known extensively explored targets susceptible to inducing resistance again. In this work, we present a new potential target for antibiotics represented by a <i>Helicobacter pylori</i> type I toxin-antitoxin system where RNA-RNA interactions are responsible for silencing the synthesis of a toxin that is lethal to bacteria and that is activated only under particular conditions. We report the design and synthesis of new RNA binders to inhibit these RNA-RNA interactions and to artificially activate toxin production and kill bacteria. After screening these compounds using several complementary assays, we identified a selective inhibitor of the targeted RNA-RNA interaction showing specific antibiotic activity against <i>H. pylori</i>. This represents an unprecedented antimicrobial strategy based on the use of compounds that are not toxic by themselves but activate the production of an endogenous toxin produced by the bacteria themselves. Finally, this work allowed us to explore new compounds to inhibit RNA-RNA interactions, which also represents an underexplored field of RNA targeting.