EMD-7870
Structure of the 50S ribosomal subunit from Methicillin Resistant Staphylococcus aureus in complex with the oxazolidinone antibiotic LZD-6
EMD-7870
Single-particle3.1 Å
Deposition: 10/05/2018
Map released: 20/03/2019
Last modified: 23/10/2024
Sample Organism:
Staphylococcus aureus
Sample: 50S Ribosomal subunit from MRSA in complex with oxazolidinone LZD-5
Fitted models: 6ddg (Avg. Q-score: 0.562)
Deposition Authors: Belousoff MJ , Venugopal H
Sample: 50S Ribosomal subunit from MRSA in complex with oxazolidinone LZD-5
Fitted models: 6ddg (Avg. Q-score: 0.562)
Deposition Authors: Belousoff MJ , Venugopal H
cryoEM-Guided Development of Antibiotics for Drug-Resistant Bacteria.
Belousoff MJ ,
Venugopal H ,
Wright A,
Seoner S,
Stuart I ,
Stubenrauch C ,
Bamert RS,
Lupton DW ,
Lithgow T
(2019) Chem Med Chem , 14 , 527 - 531
(2019) Chem Med Chem , 14 , 527 - 531
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.
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.