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.
| Original language | English |
|---|---|
| Pages (from-to) | 527-231 |
| Number of pages | 5 |
| Journal | ChemMedChem |
| Volume | 14 |
| Issue number | 5 |
| DOIs | |
| Publication status | Published - 5 Mar 2019 |
Keywords
- antibiotic resistance
- cryoEM
- linezolid
- structure-based drug design
Cite this
}
cryoEM-Guided Development of Antibiotics for Drug-Resistant Bacteria. / Belousoff, Matthew J.; Venugopal, Hari; Wright, Alexander; Seoner, Samuel; Stuart, Isabella; Stubenrauch, Chris; Bamert, Rebecca S.; Lupton, David W.; Lithgow, Trevor.
In: ChemMedChem, Vol. 14, No. 5, 05.03.2019, p. 527-231.Research output: Contribution to journal › Article › Research › peer-review
TY - JOUR
T1 - cryoEM-Guided Development of Antibiotics for Drug-Resistant Bacteria
AU - Belousoff, Matthew J.
AU - Venugopal, Hari
AU - Wright, Alexander
AU - Seoner, Samuel
AU - Stuart, Isabella
AU - Stubenrauch, Chris
AU - Bamert, Rebecca S.
AU - Lupton, David W.
AU - Lithgow, Trevor
PY - 2019/3/5
Y1 - 2019/3/5
N2 - 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.
AB - 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.
KW - antibiotic resistance
KW - cryoEM
KW - linezolid
KW - structure-based drug design
UR - http://www.scopus.com/inward/record.url?scp=85061493296&partnerID=8YFLogxK
U2 - 10.1002/cmdc.201900042
DO - 10.1002/cmdc.201900042
M3 - Article
VL - 14
SP - 527
EP - 231
JO - ChemMedChem
JF - ChemMedChem
SN - 1860-7179
IS - 5
ER -