This project approaches the increasing problem of multi-resistant, pathogenic bacterial strains with a novel and unique intervention strategy. Following a top-down approach, newly identified potential transcriptional resistance regulators from clinical isolates will be integrated into our multilevel discovery and development process consisting of deep sequencing (identification of resistance gene clusters), molecular characterization, TRIC screening (in vitro, in pathogen and in mammalian cells) and rational compound design. This will lead to the development of small drug-like compounds that allow for reactivation of licensed antibiotics.