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 journalArticleResearchpeer-review

1 Citation (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 languageEnglish
Pages (from-to)527-231
Number of pages5
JournalChemMedChem
Volume14
Issue number5
DOIs
Publication statusPublished - 5 Mar 2019

Keywords

  • antibiotic resistance
  • cryoEM
  • linezolid
  • structure-based drug design

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