Person: Purdy, Michael
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Purdy
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Michael
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Purdy, Michael
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Publication Discovery of a broad-spectrum, fluorinated macrobicyclic antibiotic through chemical synthesis(American Chemical Society (ACS), 2024-09-27) Tresco, Ben; Wu, Jun Yu Kelvin; Ramkissoon, Antonio; Aleksandrova, Elena V.; Purdy, Michael; See, Dominic N. Y.; Liu, Richard Y.; Polikanov, Yury S.; Myers, Andrew G.We report the discovery through chemical synthesis of BT-33, a fluorinated macrobicyclic oxepanoprolinamide antibiotic. BT-33 potently inhibits the growth of multidrug-resistant clinical isolates of Gram-positive and Gram-negative bacteria and has an extended half-life in vivo relative to its predecessors cresomycin and iboxamycin. We report structure-activity relationships within the macrobicyclic substructure, which reveal structural features that are essential to the enhanced potency of BT-33 as well as its increased metabolic stability. We determine the structure of BT-33 in complex with the bacterial ribosome by X-ray crystallography, analysis of which suggests that the newly introduced fluorine atom makes an additional Van der Waals contact with nucleobase G2505. Finally, we show that the C7-methyl group of BT-33 rigidifies the macrocyclic ring in a conformation that is highly preorganized for ribosomal binding by using variable-temperature 1H-NMR experiments, density-functional theory calculations, and vibrational circular dichroism spectroscopy to compare macrobicyclic homologs of BT-33 and a C7-desmethyl analog.