Structural highlights
Function
[GYRB_STAAN] DNA gyrase negatively supercoils closed circular double-stranded DNA in an ATP-dependent manner and also catalyzes the interconversion of other topological isomers of double-stranded DNA rings, including catenanes and knotted rings (By similarity).
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.
See Also
References
- ↑ Magaro' G, Prati F, Garofalo B, Corso G, Furlotti G, Apicella C, Mangano G, D'Atanasio N, Robinson D, Di Giorgio FP, Ombrato R. Virtual Screening Approach and Investigation of Structure Activity Relationships to Discover Novel Bacterial Topoisomerase Inhibitors (NBTIs) Targeting Gram-Positive and Gram-Negative Pathogens. J Med Chem. 2019 Jul 5. doi: 10.1021/acs.jmedchem.9b00394. PMID:31276392 doi:https://dx.doi.org/10.1021/acs.jmedchem.9b00394
