Journal
CHEMMEDCHEM
Volume 14, Issue 5, Pages 527-531Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/cmdc.201900042
Keywords
antibiotic resistance; cryoEM; linezolid; structure-based drug design
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Funding
- Multi-modal Australian ScienceS Imaging and Visualisation Environment (MASSIVE)
- National Health & Medical Research Council of Australia [1092262]
- Australia Research Council [DP 170103567]
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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.
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