cryoEM-Guided Development of Antibiotics for Drug-Resistant Bacteria

ChemMedChem. 2019 Mar 5;14(5):527-531. doi: 10.1002/cmdc.201900042. Epub 2019 Feb 12.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetamides / chemical synthesis*
  • Acetamides / pharmacology*
  • Anti-Bacterial Agents / chemical synthesis*
  • Anti-Bacterial Agents / pharmacology*
  • Binding Sites
  • Crystallography, X-Ray
  • Drug Design
  • Linezolid / pharmacology
  • Methicillin-Resistant Staphylococcus aureus / drug effects
  • Microbial Sensitivity Tests
  • Models, Molecular
  • Molecular Structure
  • Ribosomes / metabolism
  • Staphylococcal Infections / drug therapy
  • Structure-Activity Relationship
  • Vancomycin-Resistant Enterococci / drug effects

Substances

  • Acetamides
  • Anti-Bacterial Agents
  • acetamide
  • Linezolid