Journal article
cryoEM-Guided Development of Antibiotics for Drug-Resistant Bacteria
MJ Belousoff, H Venugopal, A Wright, S Seoner, I Stuart, C Stubenrauch, RS Bamert, DW Lupton, T Lithgow
Chemmedchem | Published : 2019
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..
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Grants
Awarded by National Institutes of Health
Funding Acknowledgements
We acknowledge the support staff and facilities at the Monash Ramaciotti Centre for Cryo-Electron Microscopy. We thank Georg Ramm for Titan Krios support, Anton Peleg for providing clinical isolates of MRSA and VRE, and Ana Traven and Jamie Rossjohn for comments on the manuscript. We acknowledge the NVIDIA Corporation for donating GPUs to aid with calculations used in this research. This work was supported by the Multi-modal Australian ScienceS Imaging and Visualisation Environment (MASSIVE) (www.massive.org.au). The work was funded by the National Health & Medical Research Council of Australia (Program Grant 1092262 to T.L.) and the Australia Research Council (DP 170103567 to D.W.L.). The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.