7RQ8

Crystal structure of the wild-type Thermus thermophilus 70S ribosome in complex with iboxamycin, mRNA, deacylated A- and E-site tRNAs, and aminoacylated P-site tRNA at 2.50A resolution

This is a non-PDB format compatible entry.

Summary for 7RQ8

• Entry DOI: 10.2210/pdb7rq8/pdb
• Descriptor: 23S Ribosomal RNA, 50S ribosomal protein L14, 50S ribosomal protein L15, ... (62 entities in total)
• Functional Keywords: iboxamycin, clindamycin, lincosamides, structure-based drug design, antibiotic, resistance, methylation, a2058, 23s rrna, 70s ribosome, inhibition of translation, peptidyl transferase center, nascent peptide exit tunnel, ribosome, ribosome-rna complex, ribosome/rna
• Biological source: Escherichia coli; More
• Total number of polymer chains: 112
• Total formula weight: 4566385.35

Authors

Mitcheltree, M.J.,Pisipati, A.,Syroegin, E.A.,Silvestre, K.J.,Klepacki, D.,Mason, J.D.,Terwilliger, D.W.,Testolin, G.,Pote, A.R.,Wu, K.J.Y.,Ladley, R.P.,Chatman, K.,Mankin, A.S.,Polikanov, Y.S.,Myers, A.G. (deposition date: 2021-08-06, release date: 2021-10-13, Last modification date: 2023-11-15)

Primary citation

Mitcheltree, M.J.,Pisipati, A.,Syroegin, E.A.,Silvestre, K.J.,Klepacki, D.,Mason, J.D.,Terwilliger, D.W.,Testolin, G.,Pote, A.R.,Wu, K.J.Y.,Ladley, R.P.,Chatman, K.,Mankin, A.S.,Polikanov, Y.S.,Myers, A.G.
A synthetic antibiotic class overcoming bacterial multidrug resistance.
Nature, 599:507-512, 2021

PubMed Abstract: 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 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 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, 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 [Formula: see text] 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.

PubMed: 34707295
DOI: 10.1038/s41586-021-04045-6

Experimental method

X-RAY DIFFRACTION (2.5 Å)