Person: Wu, Jun Yu Kelvin
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Jun Yu Kelvin
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Wu, Jun Yu Kelvin
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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.Publication A Synthetic Antibiotic Class Overcoming Bacterial Multidrug Resistance(Springer Science and Business Media LLC, 2021-10-27) Mitcheltree, Matthew; Pisipati, Amarnath; Syroegin, Egor A.; Silvestre, Katherine; Klepacki, Dorota; Mason, Jeremy; Terwilliger, Daniel; Testolin, Giambattista; Pote, Aditya; Wu, Jun Yu Kelvin; Ladley, Richard; Chatman, Kelly; Mankin, Alexander S.; Polikanov, Yury S.; Myers, AndrewThe dearth of new medicines effective against antibiotic-resistant bacteria presents a growing global public health concern . For more than five decades, the search for new antibiotics has relied heavily upon the chemical modification of natural products (semisynthesis), a method ill-equipped to combat rapidly evolving resistance threats. Semisynthetic modifications are typically of limited scope within polyfunctional antibiotics, usually increase molecular weight, and seldom permit modifications of the underlying scaffold. When properly designed, fully synthetic routes can easily address these shortcomings . Here we report the structure-guided design and component-based synthesis of a rigid oxepanoproline scaffold which, when linked to the aminooctose residue of clindamycin, produces an antibiotic of exceptional potency and spectrum of activity, here named iboxamycin. Iboxamycin is effective against ESKAPE-group pathogens including strains expressing Erm and Cfr rRNA methyltransferase enzymes, products of genes that confer resistance to all clinically relevant antibiotics targeting the large ribosomal subunit, namely macrolides, lincosamides, phenicols, oxazolidinones, pleuromutilins, and streptogramins. X-ray crystallographic studies of iboxamycin in complex with the native bacterial ribosome, as well as the Erm-methylated ribosome, uncover the structural basis for this enhanced activity, including an unforeseen and unprecedented displacement of the m2/6A2058 nucleotide upon antibiotic binding. In mice, iboxamycin is orally bioavailable, safe, and effective in treating both Gram-positive and Gram-negative bacterial infections, attesting to the capacity for chemical synthesis to provide new antibiotics in an era of rising resistance.