Binding and Action of Amino Acid Analogs of Chloramphenicol upon the Bacterial Ribosome
Abstract
Antibiotic chloramphenicol (CHL) binds with a moderate affinity at the peptidyl transferase center of the bacterial ribosome and inhibits peptide bond formation. As an approach for modifying and potentially improving properties of this inhibitor, we explored ribosome binding and inhibitory activity of a number of amino acid analogs of CHL. We report the L-histidyl analog binds to the ribosome with the affinity exceeding that of CHL by 10 fold. Several of the newly synthesized analogs were able to inhibit protein synthesis and exhibited the mode of action that was distinct from the action of CHL. However, the inhibitory properties of the semi-synthetic CHL analogs did not correlate with their affinity and in general, the amino acid analogs of CHL were less active inhibitors of translation in comparison with the original antibiotic. The X-ray crystal structures of the Thermus thermophilus 70S ribosome in complex with three semi-synthetic analogs showed that CHL derivatives bind at the peptidyl transferase center, where the aminoacyl moiety of the tested compounds established idiosyncratic interactions with rRNA. Although still fairly inefficient inhibitors of translation, the synthesized compounds represent promising chemical scaffolds that target the peptidyl transferase center of the ribosome and potentially are suitable for further exploration.
- Authors:
-
- Lomonosov Moscow State Univ., Moscow (Russia)
- Univ. of Illinois, Chicago, IL (United States)
- Lomonosov Moscow State Univ., Moscow (Russia); Skolkovo Inst. of Science and Technology (Russia)
- Lomonosov Moscow State Univ., Moscow (Russia); Russian Academy of Medical Sciences, Moscow (Russia)
- National Research Centre (NRC), Moscow (Russia). Kurchatov Inst. (NRCKI)
- (Andreyanova), Ekaterina S. [Skolkovo Inst. of Science and Technology (Russia); Lomonosov Moscow State Univ., Moscow (Russia)
- National Research Centre (NRC), Moscow (Russia). Kurchatov Inst. (NRCKI); Peter the Great St. Petersburg Polytechnic Univ., Saint Petersburg (Russia)
- Publication Date:
- Research Org.:
- Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
- Sponsoring Org.:
- National Institute of General Medical Sciences (NIGMS); National Institutes of Health (NIH); USDOE Office of Science (SC), Basic Energy Sciences (BES); Illinois State; Russian Science Foundation (RSF); Russian Foundation for Basic Research
- OSTI Identifier:
- 1434725
- Grant/Contract Number:
- S10 RR029205; S10 OD021527; AC02-06CH11357; 14-24-00061-P; 16-04-00709; 15-34-20139; R01 AI125518
- Resource Type:
- Accepted Manuscript
- Journal Name:
- Journal of Molecular Biology
- Additional Journal Information:
- Journal Volume: 430; Journal Issue: 6; Journal ID: ISSN 0022-2836
- Publisher:
- Elsevier
- Country of Publication:
- United States
- Language:
- ENGLISH
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES; antibiotic; ribosome; X-ray structure; protein synthesis; peptidyl transferase center
Citation Formats
Tereshchenkov, Andrey G., Dobosz-Bartoszek, Malgorzata, Osterman, Ilya A., Marks, James, Sergeeva, Vasilina A., Kasatsky, Pavel, Komarova, Stavrianidi, Andrey N., Rodin, Igor A., Konevega, Andrey L., Sergiev, Petr V., Sumbatyan, Natalia V., Mankin, Alexander S., Bogdanov, Alexey A., and Polikanov, Yury S. Binding and Action of Amino Acid Analogs of Chloramphenicol upon the Bacterial Ribosome. United States: N. p., 2018.
Web. doi:10.1016/j.jmb.2018.01.016.
Tereshchenkov, Andrey G., Dobosz-Bartoszek, Malgorzata, Osterman, Ilya A., Marks, James, Sergeeva, Vasilina A., Kasatsky, Pavel, Komarova, Stavrianidi, Andrey N., Rodin, Igor A., Konevega, Andrey L., Sergiev, Petr V., Sumbatyan, Natalia V., Mankin, Alexander S., Bogdanov, Alexey A., & Polikanov, Yury S. Binding and Action of Amino Acid Analogs of Chloramphenicol upon the Bacterial Ribosome. United States. https://doi.org/10.1016/j.jmb.2018.01.016
Tereshchenkov, Andrey G., Dobosz-Bartoszek, Malgorzata, Osterman, Ilya A., Marks, James, Sergeeva, Vasilina A., Kasatsky, Pavel, Komarova, Stavrianidi, Andrey N., Rodin, Igor A., Konevega, Andrey L., Sergiev, Petr V., Sumbatyan, Natalia V., Mankin, Alexander S., Bogdanov, Alexey A., and Polikanov, Yury S. Fri .
"Binding and Action of Amino Acid Analogs of Chloramphenicol upon the Bacterial Ribosome". United States. https://doi.org/10.1016/j.jmb.2018.01.016. https://www.osti.gov/servlets/purl/1434725.
@article{osti_1434725,
title = {Binding and Action of Amino Acid Analogs of Chloramphenicol upon the Bacterial Ribosome},
author = {Tereshchenkov, Andrey G. and Dobosz-Bartoszek, Malgorzata and Osterman, Ilya A. and Marks, James and Sergeeva, Vasilina A. and Kasatsky, Pavel and Komarova and Stavrianidi, Andrey N. and Rodin, Igor A. and Konevega, Andrey L. and Sergiev, Petr V. and Sumbatyan, Natalia V. and Mankin, Alexander S. and Bogdanov, Alexey A. and Polikanov, Yury S.},
abstractNote = {Antibiotic chloramphenicol (CHL) binds with a moderate affinity at the peptidyl transferase center of the bacterial ribosome and inhibits peptide bond formation. As an approach for modifying and potentially improving properties of this inhibitor, we explored ribosome binding and inhibitory activity of a number of amino acid analogs of CHL. We report the L-histidyl analog binds to the ribosome with the affinity exceeding that of CHL by 10 fold. Several of the newly synthesized analogs were able to inhibit protein synthesis and exhibited the mode of action that was distinct from the action of CHL. However, the inhibitory properties of the semi-synthetic CHL analogs did not correlate with their affinity and in general, the amino acid analogs of CHL were less active inhibitors of translation in comparison with the original antibiotic. The X-ray crystal structures of the Thermus thermophilus 70S ribosome in complex with three semi-synthetic analogs showed that CHL derivatives bind at the peptidyl transferase center, where the aminoacyl moiety of the tested compounds established idiosyncratic interactions with rRNA. Although still fairly inefficient inhibitors of translation, the synthesized compounds represent promising chemical scaffolds that target the peptidyl transferase center of the ribosome and potentially are suitable for further exploration.},
doi = {10.1016/j.jmb.2018.01.016},
journal = {Journal of Molecular Biology},
number = 6,
volume = 430,
place = {United States},
year = {Fri Feb 02 00:00:00 EST 2018},
month = {Fri Feb 02 00:00:00 EST 2018}
}
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