Abstract
DNA gyrase is an important target for the development of novel antibiotics. Although ATP-competitive DNA gyrase (GyrB) inhibitors are a well-studied class of antibacterial agents, there is currently no representative used in therapy, largely due to unwanted off-target activities. Selectivity of GyrB inhibitors against closely related human ATP-binding enzymes should be evaluated early in development to avoid off-target binding to homologous binding domains. To address this challenge, we developed selective 3D-pharmacophore models for GyrB, human topoisomerase IIα (TopoII), and the Hsp90 N-terminal domain (NTD) to be used in in silico activity profiling paradigms to identify molecules selective for GyrB over TopoII and Hsp90, as starting points for hit expansion and lead optimization. The models were used to profile highly active GyrB, TopoII, and Hsp90 inhibitors. Selected compounds were tested in in vitro assays. GyrB inhibitors 1 and 2 were inactive against TopoII and Hsp90, while 3 and 4, potent Hsp90 inhibitors, displayed no inhibition of GyrB and TopoII, and TopoII inhibitors 5 and 6 were inactive at GyrB and Hsp90. The results provide a proof of concept for the use of target activity profiling methods to identify selective starting points for hit and lead identification.
Highlights
The GyrB inhibitor novobiocin was shown to inhibit Hsp90 by binding to the C-terminal domain (CTD) allosteric site and not the N-terminal domain (NTD) ATP-binding site via the Bergerat ATP-binding fold identified by ProBiS [16,17]
A ProBiS query using E. coli GyrB (PDB ID: 4DUH) identified similar binding sites in Hsp90α, Hsp90β, and TopoIIα, which all belong to the GHKL superfamily sharing the Bergerat ATP-binding fold [39]
Competitive inhibitors of the ATP-site could potentially interact in similar identified sites, and inhibition of human topoisomerase IIα (TopoII) or Hsp90 by a bacterial DNA gyrase inhibitor poses a severe risk for unwanted damage to DNA or disruption of protein homeostasis in healthy cells
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. The increasing emergence of pathogenic bacteria resistant to antibacterial drugs is a serious threat to global health and represents the continuous need for the development of novel antibacterial agents. In 2017, the World Health Organization published a list of priority pathogens, for which new antibacterial agents are urgently needed as the currently used therapy is becoming inefficient. Resistant Pseudomonas aeruginosa, Acinetobacter baumannii, Staphylococcus aureus, Enterococcus faecium, and Enterobacteriaceae are of particular concern [1]
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