Virtual Screening Approach and Investigation of Structure Activity Relationships to Discover Novel Bacterial Topoisomerase Inhibitors (NBTIs) Targeting Gram-Positive and Gram-Negative Pathogens

Bacterial resistance is increasing rapidly, requiring urgent identification of new antibacterial drugs that are effective against multidrug-resistant pathogens. Novel bacterial topoisomerase inhibitors (NBTIs) provide a new strategy for investigating the well validated DNA gyrase and topoisomerase IV targets, while preventing cross resistance issues. On this basis, starting from a virtual screening campaign and subsequent structure-based hit optimization guided by X-ray studies, a novel class of piperazine-like NBTIs with outstanding enzymatic activity against Staphylococcus aureus and Escherichia coli DNA gyrase and topoisomerase IV was identified. Notably, compounds (±)-33, (±)-35, and (±)-36 with potent and balance multitarget enzymatic profiles, exhibited excellent efficacy against selected Gram-positive and Gram-negative pathogens, as well as clinically relevant resistant strains. Overall, the new NBTI chemotype described herein, thanks to the broad-spectrum antibacterial activity and the favourable ...