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Triphenilphosphonium Analogs of Chloramphenicol as Dual-Acting Antimicrobial and Antiproliferating Agents

In the current work, in continuation of our recent research, we synthesized and studied new chimeric compounds, including the ribosome-targeting antibiotic chloramphenicol (CHL) and the membrane-penetrating cation triphenylphosphonium (TPP), which are linked by alkyl groups of different lengths. Usi...

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Autores principales: Pavlova, Julia A., Khairullina, Zimfira Z., Tereshchenkov, Andrey G., Nazarov, Pavel A., Lukianov, Dmitrii A., Volynkina, Inna A., Skvortsov, Dmitry A., Makarov, Gennady I., Abad, Etna, Murayama, Somay Y., Kajiwara, Susumu, Paleskava, Alena, Konevega, Andrey L., Antonenko, Yuri N., Lyakhovich, Alex, Osterman, Ilya A., Bogdanov, Alexey A., Sumbatyan, Natalia V.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8145938/
https://www.ncbi.nlm.nih.gov/pubmed/33922611
http://dx.doi.org/10.3390/antibiotics10050489
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author Pavlova, Julia A.
Khairullina, Zimfira Z.
Tereshchenkov, Andrey G.
Nazarov, Pavel A.
Lukianov, Dmitrii A.
Volynkina, Inna A.
Skvortsov, Dmitry A.
Makarov, Gennady I.
Abad, Etna
Murayama, Somay Y.
Kajiwara, Susumu
Paleskava, Alena
Konevega, Andrey L.
Antonenko, Yuri N.
Lyakhovich, Alex
Osterman, Ilya A.
Bogdanov, Alexey A.
Sumbatyan, Natalia V.
author_facet Pavlova, Julia A.
Khairullina, Zimfira Z.
Tereshchenkov, Andrey G.
Nazarov, Pavel A.
Lukianov, Dmitrii A.
Volynkina, Inna A.
Skvortsov, Dmitry A.
Makarov, Gennady I.
Abad, Etna
Murayama, Somay Y.
Kajiwara, Susumu
Paleskava, Alena
Konevega, Andrey L.
Antonenko, Yuri N.
Lyakhovich, Alex
Osterman, Ilya A.
Bogdanov, Alexey A.
Sumbatyan, Natalia V.
author_sort Pavlova, Julia A.
collection PubMed
description In the current work, in continuation of our recent research, we synthesized and studied new chimeric compounds, including the ribosome-targeting antibiotic chloramphenicol (CHL) and the membrane-penetrating cation triphenylphosphonium (TPP), which are linked by alkyl groups of different lengths. Using various biochemical assays, we showed that these CAM-Cn-TPP compounds bind to the bacterial ribosome, inhibit protein synthesis in vitro and in vivo in a way similar to that of the parent CHL, and significantly reduce membrane potential. Similar to CAM-C4-TPP, the mode of action of CAM-C10-TPP and CAM-C14-TPP in bacterial ribosomes differs from that of CHL. By simulating the dynamics of CAM-Cn-TPP complexes with bacterial ribosomes, we proposed a possible explanation for the specificity of the action of these analogs in the translation process. CAM-C10-TPP and CAM-C14-TPP more strongly inhibit the growth of the Gram-positive bacteria, as compared to CHL, and suppress some CHL-resistant bacterial strains. Thus, we have shown that TPP derivatives of CHL are dual-acting compounds targeting both the ribosomes and cellular membranes of bacteria. The TPP fragment of CAM-Cn-TPP compounds has an inhibitory effect on bacteria. Moreover, since the mitochondria of eukaryotic cells possess qualities similar to those of their prokaryotic ancestors, we demonstrate the possibility of targeting chemoresistant cancer cells with these compounds.
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spelling pubmed-81459382021-05-26 Triphenilphosphonium Analogs of Chloramphenicol as Dual-Acting Antimicrobial and Antiproliferating Agents Pavlova, Julia A. Khairullina, Zimfira Z. Tereshchenkov, Andrey G. Nazarov, Pavel A. Lukianov, Dmitrii A. Volynkina, Inna A. Skvortsov, Dmitry A. Makarov, Gennady I. Abad, Etna Murayama, Somay Y. Kajiwara, Susumu Paleskava, Alena Konevega, Andrey L. Antonenko, Yuri N. Lyakhovich, Alex Osterman, Ilya A. Bogdanov, Alexey A. Sumbatyan, Natalia V. Antibiotics (Basel) Article In the current work, in continuation of our recent research, we synthesized and studied new chimeric compounds, including the ribosome-targeting antibiotic chloramphenicol (CHL) and the membrane-penetrating cation triphenylphosphonium (TPP), which are linked by alkyl groups of different lengths. Using various biochemical assays, we showed that these CAM-Cn-TPP compounds bind to the bacterial ribosome, inhibit protein synthesis in vitro and in vivo in a way similar to that of the parent CHL, and significantly reduce membrane potential. Similar to CAM-C4-TPP, the mode of action of CAM-C10-TPP and CAM-C14-TPP in bacterial ribosomes differs from that of CHL. By simulating the dynamics of CAM-Cn-TPP complexes with bacterial ribosomes, we proposed a possible explanation for the specificity of the action of these analogs in the translation process. CAM-C10-TPP and CAM-C14-TPP more strongly inhibit the growth of the Gram-positive bacteria, as compared to CHL, and suppress some CHL-resistant bacterial strains. Thus, we have shown that TPP derivatives of CHL are dual-acting compounds targeting both the ribosomes and cellular membranes of bacteria. The TPP fragment of CAM-Cn-TPP compounds has an inhibitory effect on bacteria. Moreover, since the mitochondria of eukaryotic cells possess qualities similar to those of their prokaryotic ancestors, we demonstrate the possibility of targeting chemoresistant cancer cells with these compounds. MDPI 2021-04-23 /pmc/articles/PMC8145938/ /pubmed/33922611 http://dx.doi.org/10.3390/antibiotics10050489 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Pavlova, Julia A.
Khairullina, Zimfira Z.
Tereshchenkov, Andrey G.
Nazarov, Pavel A.
Lukianov, Dmitrii A.
Volynkina, Inna A.
Skvortsov, Dmitry A.
Makarov, Gennady I.
Abad, Etna
Murayama, Somay Y.
Kajiwara, Susumu
Paleskava, Alena
Konevega, Andrey L.
Antonenko, Yuri N.
Lyakhovich, Alex
Osterman, Ilya A.
Bogdanov, Alexey A.
Sumbatyan, Natalia V.
Triphenilphosphonium Analogs of Chloramphenicol as Dual-Acting Antimicrobial and Antiproliferating Agents
title Triphenilphosphonium Analogs of Chloramphenicol as Dual-Acting Antimicrobial and Antiproliferating Agents
title_full Triphenilphosphonium Analogs of Chloramphenicol as Dual-Acting Antimicrobial and Antiproliferating Agents
title_fullStr Triphenilphosphonium Analogs of Chloramphenicol as Dual-Acting Antimicrobial and Antiproliferating Agents
title_full_unstemmed Triphenilphosphonium Analogs of Chloramphenicol as Dual-Acting Antimicrobial and Antiproliferating Agents
title_short Triphenilphosphonium Analogs of Chloramphenicol as Dual-Acting Antimicrobial and Antiproliferating Agents
title_sort triphenilphosphonium analogs of chloramphenicol as dual-acting antimicrobial and antiproliferating agents
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8145938/
https://www.ncbi.nlm.nih.gov/pubmed/33922611
http://dx.doi.org/10.3390/antibiotics10050489
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