Theemergence and spread of multidrug resistant bacteria are widelybelieved to endanger human health. New drug targets and lead compoundsexempt from cross-resistance with existing drugs are urgently needed.We report on the discovery of azaindole ureas as a novel class ofbacterial gyrase B inhibitors and detail the story of their evolutionfrom a de novodesign hit based on structure-baseddrug design. These inhibitors show potent minimum inhibitory concentrationsagainst fluoroquinolone resistant MRSAand otherGram-positive bacteria. [ABSTRACT FROM AUTHOR]