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Publication Abstract from PubMed

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 in vitro safety profile, might serve as a basis for the development of novel treatments against serious infections.

Virtual Screening Approach and Investigation of Structure Activity Relationships to Discover Novel Bacterial Topoisomerase Inhibitors (NBTIs) Targeting Gram-Positive and Gram-Negative Pathogens.,Magaro' G, Prati F, Garofalo B, Corso G, Furlotti G, Apicella C, Mangano G, D'Atanasio N, Robinson D, Di Giorgio FP, Ombrato R J Med Chem. 2019 Jul 5. doi: 10.1021/acs.jmedchem.9b00394. PMID:31276392^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.