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A Synthetic Antibiotic Scaffold Effective Against Multidrug-Resistant Bacterial Pathogens

preprint
submitted on 29.03.2021, 00:45 and posted on 30.03.2021, 06:32 by Matthew Mitcheltree, Amarnath Pisipati, Egor A. Syroegin, Katherine J. Silvestre, Dorota Klepacki, Jeremy Mason, Daniel W. Terwilliger, Giambattista Testolin, Aditya R. Pote, Kelvin J. Y. Wu, Richard Porter Ladley, Kelly Chatman, Alexander S. Mankin, Yury S. Polikanov, Andrew G. Myers
The 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 (semi-synthesis), a method ill-equipped to combat rapidly evolving resistance threats. Semi-synthetic 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 in 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 70S bacterial ribosome, as well as the Erm-methylated 70S ribosome, uncover the structural basis for this enhanced activity, including an unforeseen and unprecedented displacement of upon antibiotic binding. In mice, iboxamycin is orally bioavailable, safe, and effective in treating bacterial infections, testifying to the capacity for chemical synthesis to provide new antibiotics in an era of rising resistance.

Funding

LEO Foundation Research Grant LF18006

Blavatnik Biomedical Accelerator at Harvard University

NIH R21-AI137584

NIH R01-GM132302

NIH R35GM127134

NIH P30-GM124165

NIH-ORIP HEI S10-OD021527 (to NE-CAT)

DOE Office of Science Coronavirus CARES Act

NSF Graduate Research Fellowship DGE1144152

A*STAR National Science Scholarship

Deutsche Forschungsgemeinschaft TE1311-1-1

History

Email Address of Submitting Author

m.mitcheltree@gmail.com

Institution

Harvard University

Country

United States of America

ORCID For Submitting Author

0000-0003-3774-628X

Declaration of Conflict of Interest

A.G.M., M.J.M., K.J.S., J.D.M., and G.T are inventors in a provisional patent application submitted by the President and Fellows of Harvard College covering antibiotics of the type described in this work. A.G.M., M.J.M., and K.J.S. have filed an international patent application WO/2019/032936 ‘Lincosamide Antibiotics and Uses Thereof’. A.G.M. and M.J.M. have filed an international patent application WO/2019/032956 ‘Lincosamide Antibiotics and Uses Thereof”.

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