Virtual Screening Approach and Investigation of Structure–Activity Relationships To Discover Novel Bacterial Topoisomerase Inhibitors 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
balanced 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, owing to the broad-spectrum antibacterial activity
and favorable in vitro safety profile, might serve as a basis for
the development of novel treatments against serious infections.