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Unifying the Aminohexopyranose‐ and Peptidyl‐Nucleoside Antibiotics: Implications for Antibiotic Design
Author(s) -
Serrano Catherine M.,
Kanna Reddy Hariprasada Reddy,
Eiler Daniel,
Koch Michael,
Tresco Ben I. C.,
Barrows Louis R.,
VanderLinden Ryan T.,
Testa Charles A.,
Sebahar Paul R.,
Looper Ryan E.
Publication year - 2020
Publication title -
angewandte chemie
Language(s) - English
Resource type - Journals
eISSN - 1521-3757
pISSN - 0044-8249
DOI - 10.1002/ange.202003094
Subject(s) - thermus thermophilus , peptidyl transferase , ribosome , chemistry , 50s , stereochemistry , 30s , protein subunit , ribosomal rna , nucleoside , translation (biology) , binding site , combinatorial chemistry , biochemistry , rna , gene , escherichia coli , messenger rna
Abstract In search of new anti‐tuberculars compatible with anti‐retroviral therapy we re‐identified amicetin as a lead compound. Amicetin's binding to the 70S ribosomal subunit of Thermus thermophilus ( Tth ) has been unambiguously determined by crystallography and reveals it to occupy the peptidyl transferase center P‐site of the ribosome. The amicetin binding site overlaps significantly with that of the well‐known protein synthesis inhibitor balsticidin S. Amicetin, however, is the first compound structurally characterized to bind to the P‐site with demonstrated selectivity for the inhibition of prokaryotic translation. The natural product‐ribosome structure enabled the synthesis of simplified analogues that retained both potency and selectivity for the inhibition of prokaryotic translation.