pt0c00041_si_001.pdf (1.13 MB)
Characterization of the Core Ribosomal Binding Region for the Oxazolidone Family of Antibiotics Using Cryo-EM
journal contribution
posted on 2020-05-19, 20:08 authored by Alexander Wright, Kieran Deane-Alder, Edward Marschall, Rebecca Bamert, Hari Venugopal, Trevor Lithgow, David W. Lupton, Matthew J. BelousoffLinezolid and tedizolid are oxazolidinones
with established clinical
utility for the treatment of Gram-positive pathogens. Over time it
has become apparent that even modest structural changes to the core
phenyl oxazolidinone leads to drastic changes in biological activity.
Consequently, the structure–activity relationship around the
core oxazolidinone is constantly evolving, often reflected with new
structural motifs present in nascent oxazolidinones. Herein we describe
the use of cryo-electron microscopy to examine the differences in
binding of several functionally different oxazolidinones in the hopes
of enhanced understanding of their SAR. Tedizolid, radezolid, T145,
and contezolid have been examined within the peptidyl transferase
center (PTC) of the 50S ribosomal subunit from methicillin resistant Staphylococcus aureus. The ribosome–antibiotic complexes
were resolved to a resolution of around 3 Å enabling unambiguous
assignment of how each antibiotic interacts with the PTC.