title: Fragment-based discovery of DNA gyrase inhibitors targeting the ATPase subunit of GyrB.
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.
authors.affiliation: Cubist Pharmaceuticals, 65 Hayden Ave., Lexington, MA 02421, United States.
authors.forename: Michael F
authors.initials: MF
authors.lastname: Mesleh
authors.affiliation: Cubist Pharmaceuticals, 65 Hayden Ave., Lexington, MA 02421, United States.
authors.forename: Jason B
authors.initials: JB
authors.lastname: Cross
authors.affiliation: Cubist Pharmaceuticals, 65 Hayden Ave., Lexington, MA 02421, United States.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Evotec AG, Manfred Eigen Campus, Essener Bogen 7, 22419 Hamburg, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Kahmann
authors.affiliation: Evotec (UK) Ltd., 114 Innovation Drive, Milton Park, Abingdon OX14 4RZ, UK.
authors.forename: Ole A
authors.initials: OA
authors.lastname: Andersen
authors.affiliation: Evotec (UK) Ltd., 114 Innovation Drive, Milton Park, Abingdon OX14 4RZ, UK.
authors.forename: John
authors.initials: J
authors.lastname: Barker
authors.affiliation: Evotec (UK) Ltd., 114 Innovation Drive, Milton Park, Abingdon OX14 4RZ, UK.
authors.forename: Robert K
authors.initials: RK
authors.lastname: Cheng
authors.affiliation: Evotec (UK) Ltd., 114 Innovation Drive, Milton Park, Abingdon OX14 4RZ, UK.
authors.forename: Brunella
authors.initials: B
authors.lastname: Felicetti
authors.affiliation: Evotec (UK) Ltd., 114 Innovation Drive, Milton Park, Abingdon OX14 4RZ, UK.
authors.forename: Michael
authors.initials: M
authors.lastname: Wood
authors.affiliation: Evotec (UK) Ltd., 114 Innovation Drive, Milton Park, Abingdon OX14 4RZ, UK.
authors.forename: Andrea T
authors.initials: AT
authors.lastname: Hadfield
authors.affiliation: Evotec AG, Manfred Eigen Campus, Essener Bogen 7, 22419 Hamburg, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Scheich
authors.affiliation: Cubist Pharmaceuticals, 65 Hayden Ave., Lexington, MA 02421, United States.
authors.forename: Terence I
authors.initials: TI
authors.lastname: Moy
authors.affiliation: Cubist Pharmaceuticals, 65 Hayden Ave., Lexington, MA 02421, United States.
authors.forename: Qingyi
authors.initials: Q
authors.lastname: Yang
authors.affiliation: Cubist Pharmaceuticals, 65 Hayden Ave., Lexington, MA 02421, United States.
authors.forename: Joseph
authors.initials: J
authors.lastname: Shotwell
authors.affiliation: Cubist Pharmaceuticals, 65 Hayden Ave., Lexington, MA 02421, United States.
authors.forename: Kien
authors.initials: K
authors.lastname: Nguyen
authors.affiliation: Cubist Pharmaceuticals, 65 Hayden Ave., Lexington, MA 02421, United States.
authors.forename: Blaise
authors.initials: B
authors.lastname: Lippa
authors.affiliation: Cubist Pharmaceuticals, 65 Hayden Ave., Lexington, MA 02421, United States.
authors.forename: Roland
authors.initials: R
authors.lastname: Dolle
authors.affiliation: Cubist Pharmaceuticals, 65 Hayden Ave., Lexington, MA 02421, United States.
authors.forename: M Dominic
authors.initials: MD
authors.lastname: Ryan
mesh_terms: D000251:Adenosine Triphosphatases / Q000378:metabolism; D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000378:metabolism; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001665:Binding Sites; D018360:Crystallography, X-Ray; D027081:DNA Gyrase / Q000737:chemistry* / Q000378:metabolism; D027101:DNA Topoisomerase IV / Q000037:antagonists & inhibitors / Q000378:metabolism; D015195:Drug Design; D004926:Escherichia coli / Q000378:metabolism; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D013211:Staphylococcus aureus / Q000201:enzymology; D059005:Topoisomerase II Inhibitors / Q000737:chemistry* / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D008024:Ligands; D059005:Topoisomerase II Inhibitors; D000251:Adenosine Triphosphatases; D027101:DNA Topoisomerase IV; D027081:DNA Gyrase
keywords: DNA gyrase; Fragment-based screening; GyrB; NMR; Structure-based design