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Title | cryoEM-Guided Development of Antibiotics for Drug-Resistant Bacteria. |
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Journal, issue, pages | ChemMedChem, Vol. 14, Issue 5, Page 527-531, Year 2019 |
Publish date | Mar 5, 2019 |
Authors | Matthew J Belousoff / Hari Venugopal / Alexander Wright / Samuel Seoner / Isabella Stuart / Chris Stubenrauch / Rebecca S Bamert / David W Lupton / Trevor Lithgow / |
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 ...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. |
External links | ChemMedChem / PubMed:30667174 |
Methods | EM (single particle) |
Resolution | 3.1 Å |
Structure data | |
Chemicals | ChemComp-G6V: ChemComp-G6M: |
Source |
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Keywords | Ribosome/Antibiotic / antibiotic complex / linezolid / oxazolidinone / 50S / ribosome / Ribosome-Antibiotic complex |