A synthetic antibiotic class overcoming bacterial multidrug resistance

Matthew J. Mitcheltree, Amarnath Pisipati, Egor A. Syroegin, Katherine J. Silvestre, Dorota Klepacki, Jeremy D. Mason, Daniel W. Terwilliger, Giambattista Testolin, Aditya R. Pote, Kelvin J. Y. Wu, Richard Porter Ladley, Kelly Chatman, Alexander S. Mankin, Yury S. Polikanov () and Andrew G. Myers ()
Additional contact information
Matthew J. Mitcheltree: Harvard University
Amarnath Pisipati: Harvard University
Egor A. Syroegin: University of Illinois at Chicago
Katherine J. Silvestre: Harvard University
Dorota Klepacki: University of Illinois at Chicago
Jeremy D. Mason: Harvard University
Daniel W. Terwilliger: Harvard University
Giambattista Testolin: Harvard University
Aditya R. Pote: Harvard University
Kelvin J. Y. Wu: Harvard University
Richard Porter Ladley: Harvard University
Kelly Chatman: Harvard University
Alexander S. Mankin: University of Illinois at Chicago
Yury S. Polikanov: University of Illinois at Chicago
Andrew G. Myers: Harvard University

Nature, 2021, vol. 599, issue 7885, 507-512

Abstract: Abstract The dearth of new medicines effective against antibiotic-resistant bacteria presents a growing global public health concern1. For more than five decades, the search for new antibiotics has relied heavily on 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 shortcomings2. 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, which we name iboxamycin. Iboxamycin is effective against ESKAPE pathogens including strains expressing Erm and Cfr ribosomal RNA 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 with the Erm-methylated ribosome, uncover the structural basis for this enhanced activity, including a displacement of the $${\text{m}}_{2}^{6}\text{A}2058$$ m 2 6 A 2058 nucleotide upon antibiotic binding. Iboxamycin is orally bioavailable, safe and effective in treating both Gram-positive and Gram-negative bacterial infections in mice, attesting to the capacity for chemical synthesis to provide new antibiotics in an era of increasing resistance.

Date: 2021
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DOI: 10.1038/s41586-021-04045-6

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