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Download fileVirtual Screening Approach and Investigation of Structure–Activity Relationships To Discover Novel Bacterial Topoisomerase Inhibitors Targeting Gram-Positive and Gram-Negative Pathogens
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posted 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 OmbratoBacterial
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.
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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