jm9b00394_si_003.pdb (1.9 MB)
Download file

Virtual Screening Approach and Investigation of Structure–Activity Relationships To Discover Novel Bacterial Topoisomerase Inhibitors Targeting Gram-Positive and Gram-Negative Pathogens

Download (1.9 MB)
dataset
posted on 29.07.2019, 21:30 authored by Gabriele Magarò, Federica Prati, Barbara Garofalo, Gaia Corso, Guido Furlotti, Claudia Apicella, Giorgina Mangano, Noemi D’Atanasio, Daniel Robinson, Francesco Paolo Di Giorgio, Rosella Ombrato
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.

History