[thread] It's finally here! We used chemical synthesis and cutting-edge cryo-EM to engineer streptogramin antibiotics that overcome an ancient resistance mechanism. The story is out today in @nature, and I'll provide a brief summary here. 1/8 
Dr. Qi Li developed the route and led the chemistry team. Jenna Pellegrino and @d_john_lee in @fraser_lab pushed the limits of ribosome cryo-EM. Over a dozen other co-authors from four continents contributed. Special thanks to Daniel Blair and Marty Burke for the @NatureNews! 2/8
Streptogramin antibiotics comprise two structural sub-classes: group A and group B. A primary resistance mechanism for group A streptogramins is deactivation by Vat proteins. These acetylate the C14 alcohol in the 23-membered macrocycle, preventing binding to the ribosome. 3/8
We developed a fully synthetic route and used it to synthesize over 70 streptogramins with unprecedented structural variability. We focused on modifications that we hypothesized would maintain (or improve) ribosomal binding while disrupting deactivation by Vats. 4/8
We found modifications at two sites (at C3 and C4) that improved activity compared to other streptogramins, especially in Vat strains. Our most potent compound (47) was ~16-fold more active than other streptogramins, and was acetylated more slowly in vitro. 5/8
In mice infected with VatA S. aureus, compound 47 reduced the bacterial load by ~100-fold, almost back to pre-treatment levels (2 h). This was ~10-fold more effective than flopristin, the most potent streptogramin prior to this work. 6/8
@fraser_lab was able to characterize the binding of C3 and C4 analogs to the bacterial ribosome using cryo-EM, providing a detailed molecular picture of where the C3 and C4 sidechains reside in relation to the catalytic center and to group B streptogramins. 7/8
Most importantly, the catalytic center of the bacterial ribosome is a privileged binding site for dozens of classes of antibiotics, and we hope that our discoveries can be used to inform the optimization of other classes. This is just the start!! 8/8
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