SNAP output for PDB entry 6fm4 [SNAP web server]

PDB-id

6fm4; SNAP-derived features in text and JSON formats; DNAproDB

Class

isomerase

Method

X-ray (2.7 Å)

Summary

The crystal structure of s. aureus gyrase complex with id-130 and DNA

Reference

Magaro G, Prati F, Garofalo B, Corso G, Furlotti G, Apicella C, Mangano G, D'Atanasio N, Robinson D, Di Giorgio FP, Ombrato R (2019): "Virtual Screening Approach and Investigation of Structure-Activity Relationships To Discover Novel Bacterial Topoisomerase Inhibitors Targeting Gram-Positive and Gram-Negative Pathogens." J.Med.Chem., 62, 7445-7472. doi: 10.1021/acs.jmedchem.9b00394.

Abstract

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.