Virtual Screening Approach and Investigation of Structure–Activity Relationships To Discover Novel Bacterial Topoisomerase Inhibitors Targeting Gram-Positive and Gram-Negative Pathogens
datasetposted on 2019-07-29, 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.
Read the peer-reviewed publication
Gram-Negative PathogensStaphylococcus aureuscross-resistance issuesTopoisomerase Inhibitors Targeting Gram-PositiveNBTI chemotypetopoisomerase IVnovel treatmentsbasisGram-negative pathogensnovel classEscherichia coli DNA gyrasetopoisomerase inhibitorstopoisomerase IV targetssafety profilemultidrug-resistant pathogensX-ray studiespiperazine-like NBTIsVirtual Screening Approachwell-validated DNA gyrasescreening campaignDiscover Novel