6DDD

Structure of the 50S ribosomal subunit from Methicillin Resistant Staphylococcus aureus in complex with the oxazolidinone antibiotic LZD-5

Summary for 6DDD

• Entry DOI: 10.2210/pdb6ddd/pdb
• Related: 6DDG
• EMDB information: 7867 7870
• Descriptor: 50S ribosomal protein L19, 50S ribosomal protein L28, 50S ribosomal protein L29, ... (28 entities in total)
• Functional Keywords: antibiotic complex, linezolid, oxazolidinone, 50s, ribosome, ribosome-antibiotic complex, ribosome/antibiotic
• Biological source: Staphylococcus aureus; More
• Total number of polymer chains: 27
• Total formula weight: 1306943.55

Authors

Belousoff, M.J.,Venugopal, H.,Bamert, R.S.,Lithgow, T. (deposition date: 2018-05-10, release date: 2019-03-20, Last modification date: 2024-10-16)

Primary citation

Belousoff, M.J.,Venugopal, H.,Wright, A.,Seoner, S.,Stuart, I.,Stubenrauch, C.,Bamert, R.S.,Lupton, D.W.,Lithgow, T.
cryoEM-Guided Development of Antibiotics for Drug-Resistant Bacteria.
ChemMedChem, 14:527-531, 2019

PubMed 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.

PubMed: 30667174
DOI: 10.1002/cmdc.201900042

Experimental method

ELECTRON MICROSCOPY (3.1 Å)