cryoEM-Guided Development of Antibiotics for Drug-Resistant Bacteria
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.
Belousoff, Matthew J.,Venugopal, Hari,Wright, Alexander,Seoner, Samuel,Stuart, Isabella,Stubenrauch, Chris,Bamert, Rebecca S.,Lupton, David W.,Lithgow, Trevor
Oxazolidinone antibacterial agents having a thiocarbonyl functionality
The present invention provides compounds of Formula 1: or pharmaceutical acceptable salts thereof wherein A, G and R1are as defined in the claims which are antibacterial agents.
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(2010/01/30)
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