6FM4

The crystal structure of S. aureus Gyrase complex with ID-130 and DNA

Summary for 6FM4

• Entry DOI: 10.2210/pdb6fm4/pdb
• Descriptor: DNA gyrase subunit B,DNA gyrase subunit B,DNA gyrase subunit A, DNA (5'-5UA*D(P*GP*CP*CP*GP*TP*AP*GP*GP*GP*CP*CP*CP*TP*AP*CP*GP*GP*CP*T)-3'), DNA (5'-5UA*D(P*GP*CP*CP*GP*TP*AP*GP*GP*GP*CP*CP*CP*TP*AP*CP*GP*GP*C)-3'), ... (7 entities in total)
• Functional Keywords: nbtis, bacterial topoisomerase, gyrase, isomerase
• Biological source: Staphylococcus aureus (strain N315); More
• Total number of polymer chains: 4
• Total formula weight: 168689.10

Authors

Ombrato, R.,Garofalo, B.,Mangano, G.,Mancini, F. (deposition date: 2018-01-30, release date: 2019-07-10, Last modification date: 2024-01-17)

Primary citation

Magaro, G.,Prati, F.,Garofalo, B.,Corso, G.,Furlotti, G.,Apicella, C.,Mangano, G.,D'Atanasio, N.,Robinson, D.,Di Giorgio, F.P.,Ombrato, R.
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, 2019

PubMed 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 and DNA gyrase and topoisomerase IV was identified. Notably, compounds , , and 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.

PubMed: 31276392
DOI: 10.1021/acs.jmedchem.9b00394

Experimental method

X-RAY DIFFRACTION (2.7 Å)