cryoEM-Guided Development of Antibiotics for Drug-Resistant Bacteria

Matthew J. Belousoff; Hari Venugopal; Alexander Wright; Samuel Seoner; Isabella Stuart; Chris Stubenrauch; Rebecca S. Bamert; David W. Lupton; Trevor Lithgow

doi:10.1002/cmdc.201900042

cryoEM-Guided Development of Antibiotics for Drug-Resistant Bacteria

Matthew J. Belousoff, Hari Venugopal, Alexander Wright, Samuel Seoner, Isabella Stuart, Chris Stubenrauch, Rebecca S. Bamert, David W. Lupton, Trevor Lithgow

Research output: Contribution to journal › Article › Research › peer-review

3 Citations (Scopus)

Abstract

While the ribosome is a common target for antibiotics, challenges with crystallography can impede the development of new bioactives using structure-based drug design approaches. In this study we exploit common structural features present in linezolid-resistant forms of both methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus (VRE) to redesign the antibiotic. Enabled by rapid and facile cryoEM structures, this process has identified (S)-2,2-dichloro-N-((3-(3-fluoro-4-morpholinophenyl)-2-oxooxazolidin-5-yl)methyl)acetamide (LZD-5) and (S)-2-chloro-N-((3-(3-fluoro-4-morpholinophenyl)-2-oxooxazolidin-5-yl)methyl) acetamide (LZD-6), which inhibit the ribosomal function and growth of linezolid-resistant MRSA and VRE. The strategy discussed highlights the potential for cryoEM to facilitate the development of novel bioactive materials.

Original language	English
Pages (from-to)	527-231
Number of pages	5
Journal	ChemMedChem
Volume	14
Issue number	5
DOIs	https://doi.org/10.1002/cmdc.201900042
Publication status	Published - 5 Mar 2019

Keywords

antibiotic resistance
cryoEM
linezolid
structure-based drug design

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10.1002/cmdc.201900042

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Ramaciotti Centre for Cryo-Electron Microscopy
Georg Ramm (Manager), Viola M.J. Oorschot (Operator), Simon Andrew Crawford (Operator), Hariprasad Venugopal (Operator), Joan Marea Clark (Operator) & Gediminas Gervinskas (Operator)
Office of the Vice-Provost (Research and Research Infrastructure)
Facility/equipment: Facility

Cite this

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title = "cryoEM-Guided Development of Antibiotics for Drug-Resistant Bacteria",

abstract = "While the ribosome is a common target for antibiotics, challenges with crystallography can impede the development of new bioactives using structure-based drug design approaches. In this study we exploit common structural features present in linezolid-resistant forms of both methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus (VRE) to redesign the antibiotic. Enabled by rapid and facile cryoEM structures, this process has identified (S)-2,2-dichloro-N-((3-(3-fluoro-4-morpholinophenyl)-2-oxooxazolidin-5-yl)methyl)acetamide (LZD-5) and (S)-2-chloro-N-((3-(3-fluoro-4-morpholinophenyl)-2-oxooxazolidin-5-yl)methyl) acetamide (LZD-6), which inhibit the ribosomal function and growth of linezolid-resistant MRSA and VRE. The strategy discussed highlights the potential for cryoEM to facilitate the development of novel bioactive materials.",

keywords = "antibiotic resistance, cryoEM, linezolid, structure-based drug design",

author = "Belousoff, {Matthew J.} and Hari Venugopal and Alexander Wright and Samuel Seoner and Isabella Stuart and Chris Stubenrauch and Bamert, {Rebecca S.} and Lupton, {David W.} and Trevor Lithgow",

year = "2019",

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cryoEM-Guided Development of Antibiotics for Drug-Resistant Bacteria. / Belousoff, Matthew J.; Venugopal, Hari; Wright, Alexander; Seoner, Samuel; Stuart, Isabella; Stubenrauch, Chris; Bamert, Rebecca S.; Lupton, David W.; Lithgow, Trevor.

In: ChemMedChem, Vol. 14, No. 5, 05.03.2019, p. 527-231.

Research output: Contribution to journal › Article › Research › peer-review

TY - JOUR

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AU - Belousoff, Matthew J.

AU - Venugopal, Hari

AU - Wright, Alexander

AU - Seoner, Samuel

AU - Stuart, Isabella

AU - Stubenrauch, Chris

AU - Bamert, Rebecca S.

AU - Lupton, David W.

AU - Lithgow, Trevor

PY - 2019/3/5

Y1 - 2019/3/5

N2 - While the ribosome is a common target for antibiotics, challenges with crystallography can impede the development of new bioactives using structure-based drug design approaches. In this study we exploit common structural features present in linezolid-resistant forms of both methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus (VRE) to redesign the antibiotic. Enabled by rapid and facile cryoEM structures, this process has identified (S)-2,2-dichloro-N-((3-(3-fluoro-4-morpholinophenyl)-2-oxooxazolidin-5-yl)methyl)acetamide (LZD-5) and (S)-2-chloro-N-((3-(3-fluoro-4-morpholinophenyl)-2-oxooxazolidin-5-yl)methyl) acetamide (LZD-6), which inhibit the ribosomal function and growth of linezolid-resistant MRSA and VRE. The strategy discussed highlights the potential for cryoEM to facilitate the development of novel bioactive materials.

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cryoEM-Guided Development of Antibiotics for Drug-Resistant Bacteria

Abstract

Keywords

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Ramaciotti Centre for Cryo-Electron Microscopy

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