Fragment-based discovery of DNA gyrase inhibitors targeting the ATPase subunit of GyrB

Bioorganic & Medicinal Chemistry Letters
Michael F MeslehM Dominic Ryan

Abstract

Inhibitors of the ATPase function of bacterial DNA gyrase, located in the GyrB subunit and its related ParE subunit in topoisomerase IV, have demonstrated antibacterial activity. In this study we describe an NMR fragment-based screening effort targeting Staphylococcus aureus GyrB that identified several attractive and novel starting points with good ligand efficiency. Fragment hits were further characterized using NMR binding studies against full-length S. aureus GyrB and Escherichia coli ParE. X-ray co-crystal structures of select fragment hits confirmed binding and suggested a path for medicinal chemistry optimization. The identification, characterization, and elaboration of one of these fragment series to a 0.265 μM inhibitor is described herein.

References

Oct 6, 2005·Bioorganic & Medicinal Chemistry Letters·Marko OblakTomaz Solmajer
Aug 8, 2007·Antimicrobial Agents and Chemotherapy·David A OstrovThomas C Rowe
Jan 5, 2010·Bioorganic & Medicinal Chemistry Letters·Matjaz BrvarTom Solmajer

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Citations

Apr 21, 2016·ACS Medicinal Chemistry Letters·Jason B CrossRoland E Dolle
Jun 11, 2016·Future Medicinal Chemistry·Yuk-Ching Tse-Dinh
May 23, 2018·Future Medicinal Chemistry·Michaela BarančokováJanez Ilaš
Jan 29, 2019·Expert Opinion on Therapeutic Patents·Martina DurcikJanez Ilaš
Feb 12, 2021·Nanoscale Research Letters·Muhammad Shahid SharifAlvina Rafiq Butt
Nov 1, 2017·Journal of Medicinal Chemistry·Christopher N JohnsonDavid C Rees

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