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

Michael F. Mesleh; Jason B. Cross; Jing Zhang; Jan Kahmann; Ole A. Andersen; John Barker; Robert K. Cheng; Brunella Felicetti; Michael Wood; Andrea T. Hadfield; Christoph Scheich; Terence I. Moy; Qingyi Yang; Joseph Shotwell; Kien Nguyen; Blaise Lippa; Roland Dolle; M. Dominic Ryan

doi:10.1016/j.bmcl.2016.01.009

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

Michael F. Mesleh, Jason B. Cross, Jing Zhang, Jan Kahmann, Ole A. Andersen, John Barker, Robert K. Cheng, Brunella Felicetti, Michael Wood, Andrea T. Hadfield, Christoph Scheich, Terence I. Moy, Qingyi Yang, Joseph Shotwell, Kien Nguyen, Blaise Lippa, Roland Dolle, M. Dominic Ryan

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47 Scopus citations

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.

Original language	English
Pages (from-to)	1314-1318
Number of pages	5
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	26
Issue number	4
DOIs	https://doi.org/10.1016/j.bmcl.2016.01.009
State	Published - Feb 15 2016

Keywords

DNA gyrase
Fragment-based screening
GyrB
NMR
Structure-based design

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Mesleh, M. F., Cross, J. B., Zhang, J., Kahmann, J., Andersen, O. A., Barker, J., Cheng, R. K., Felicetti, B., Wood, M., Hadfield, A. T., Scheich, C., Moy, T. I., Yang, Q., Shotwell, J., Nguyen, K., Lippa, B., Dolle, R., & Ryan, M. D. (2016). Fragment-based discovery of DNA gyrase inhibitors targeting the ATPase subunit of GyrB. Bioorganic and Medicinal Chemistry Letters, 26(4), 1314-1318. https://doi.org/10.1016/j.bmcl.2016.01.009

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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.",

keywords = "DNA gyrase, Fragment-based screening, GyrB, NMR, Structure-based design",

author = "Mesleh, {Michael F.} and Cross, {Jason B.} and Jing Zhang and Jan Kahmann and Andersen, {Ole A.} and John Barker and Cheng, {Robert K.} and Brunella Felicetti and Michael Wood and Hadfield, {Andrea T.} and Christoph Scheich and Moy, {Terence I.} and Qingyi Yang and Joseph Shotwell and Kien Nguyen and Blaise Lippa and Roland Dolle and Ryan, {M. Dominic}",

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doi = "10.1016/j.bmcl.2016.01.009",

language = "English",

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Mesleh, MF, Cross, JB, Zhang, J, Kahmann, J, Andersen, OA, Barker, J, Cheng, RK, Felicetti, B, Wood, M, Hadfield, AT, Scheich, C, Moy, TI, Yang, Q, Shotwell, J, Nguyen, K, Lippa, B, Dolle, R & Ryan, MD 2016, 'Fragment-based discovery of DNA gyrase inhibitors targeting the ATPase subunit of GyrB', Bioorganic and Medicinal Chemistry Letters, vol. 26, no. 4, pp. 1314-1318. https://doi.org/10.1016/j.bmcl.2016.01.009

TY - JOUR

T1 - Fragment-based discovery of DNA gyrase inhibitors targeting the ATPase subunit of GyrB

AU - Mesleh, Michael F.

AU - Cross, Jason B.

AU - Zhang, Jing

AU - Kahmann, Jan

AU - Andersen, Ole A.

AU - Barker, John

AU - Cheng, Robert K.

AU - Felicetti, Brunella

AU - Wood, Michael

AU - Hadfield, Andrea T.

AU - Scheich, Christoph

AU - Moy, Terence I.

AU - Yang, Qingyi

AU - Shotwell, Joseph

AU - Nguyen, Kien

AU - Lippa, Blaise

AU - Dolle, Roland

AU - Ryan, M. Dominic

PY - 2016/2/15

Y1 - 2016/2/15

N2 - 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.

AB - 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.

KW - DNA gyrase

KW - Fragment-based screening

KW - GyrB

KW - NMR

KW - Structure-based design

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U2 - 10.1016/j.bmcl.2016.01.009

DO - 10.1016/j.bmcl.2016.01.009

M3 - Article

C2 - 26786695

AN - SCOPUS:84958110499

SN - 0960-894X

VL - 26

SP - 1314

EP - 1318

JO - Bioorganic and Medicinal Chemistry Letters

JF - Bioorganic and Medicinal Chemistry Letters

IS - 4

ER -

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

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Keywords

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