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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MDPI AG
2021-04-01
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Series: | Antibiotics |
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Online Access: | https://www.mdpi.com/2079-6382/10/5/489 |
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language |
English |
format |
Article |
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DOAJ |
author |
Julia A. Pavlova Zimfira Z. Khairullina Andrey G. Tereshchenkov Pavel A. Nazarov Dmitrii A. Lukianov Inna A. Volynkina Dmitry A. Skvortsov Gennady I. Makarov Etna Abad Somay Y. Murayama Susumu Kajiwara Alena Paleskava Andrey L. Konevega Yuri N. Antonenko Alex Lyakhovich Ilya A. Osterman Alexey A. Bogdanov Natalia V. Sumbatyan |
spellingShingle |
Julia A. Pavlova Zimfira Z. Khairullina Andrey G. Tereshchenkov Pavel A. Nazarov Dmitrii A. Lukianov Inna A. Volynkina Dmitry A. Skvortsov Gennady I. Makarov Etna Abad Somay Y. Murayama Susumu Kajiwara Alena Paleskava Andrey L. Konevega Yuri N. Antonenko Alex Lyakhovich Ilya A. Osterman Alexey A. Bogdanov Natalia V. Sumbatyan Triphenilphosphonium Analogs of Chloramphenicol as Dual-Acting Antimicrobial and Antiproliferating Agents Antibiotics chloramphenicol alkyl(triphenyl)phosphonium bacterial ribosome molecular dynamics simulations antibiotic activity antiproliferative activity |
author_facet |
Julia A. Pavlova Zimfira Z. Khairullina Andrey G. Tereshchenkov Pavel A. Nazarov Dmitrii A. Lukianov Inna A. Volynkina Dmitry A. Skvortsov Gennady I. Makarov Etna Abad Somay Y. Murayama Susumu Kajiwara Alena Paleskava Andrey L. Konevega Yuri N. Antonenko Alex Lyakhovich Ilya A. Osterman Alexey A. Bogdanov Natalia V. Sumbatyan |
author_sort |
Julia A. Pavlova |
title |
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_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_sort |
triphenilphosphonium analogs of chloramphenicol as dual-acting antimicrobial and antiproliferating agents |
publisher |
MDPI AG |
series |
Antibiotics |
issn |
2079-6382 |
publishDate |
2021-04-01 |
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. |
topic |
chloramphenicol alkyl(triphenyl)phosphonium bacterial ribosome molecular dynamics simulations antibiotic activity antiproliferative activity |
url |
https://www.mdpi.com/2079-6382/10/5/489 |
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doaj-d7e64d55801f418cb67a84cf4c2c37fb2021-04-23T23:03:26ZengMDPI AGAntibiotics2079-63822021-04-011048948910.3390/antibiotics10050489Triphenilphosphonium Analogs of Chloramphenicol as Dual-Acting Antimicrobial and Antiproliferating AgentsJulia A. Pavlova0Zimfira Z. Khairullina1Andrey G. Tereshchenkov2Pavel A. Nazarov3Dmitrii A. Lukianov4Inna A. Volynkina5Dmitry A. Skvortsov6Gennady I. Makarov7Etna Abad8Somay Y. Murayama9Susumu Kajiwara10Alena Paleskava11Andrey L. Konevega12Yuri N. Antonenko13Alex Lyakhovich14Ilya A. Osterman15Alexey A. Bogdanov16Natalia V. Sumbatyan17Department of Chemistry, Lomonosov Moscow State University, Leninskie Gory 1, 119991 Moscow, RussiaDepartment of Chemistry, Lomonosov Moscow State University, Leninskie Gory 1, 119991 Moscow, RussiaA.N. Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Leninskie Gory 1, 119992 Moscow, RussiaA.N. Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Leninskie Gory 1, 119992 Moscow, RussiaCenter of Life Sciences, Skolkovo Institute of Science and Technology, 143028 Skolkovo, RussiaSchool of Bioengineering and Bioinformatics, Lomonosov Moscow State University, 119992 Moscow, RussiaDepartment of Chemistry, Lomonosov Moscow State University, Leninskie Gory 1, 119991 Moscow, RussiaLaboratory of the Multiscale Modeling of Multicomponent Materials, South Ural State University, 454080 Chelyabinsk, RussiaDepartment of Experimental and Health Sciences, Universitat Pompeu Fabra, 08003 Barcelona, SpainDepartment of Chemotherapy and Mycoses, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku-ku, Tokyo 162-8340, JapanSchool of Life Science and Technology, Tokyo Institute of Technology, Yokohama, Kanagawa 226-8501, JapanPetersburg Nuclear Physics Institute, NRC “Kurchatov Institute”, 188300 Gatchina, RussiaPetersburg Nuclear Physics Institute, NRC “Kurchatov Institute”, 188300 Gatchina, RussiaA.N. Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Leninskie Gory 1, 119992 Moscow, RussiaInstitute of Molecular Biology and Biophysics, Federal Research Center of Fundamental and Translational Medicine, 630117 Novosibirsk, RussiaDepartment of Chemistry, Lomonosov Moscow State University, Leninskie Gory 1, 119991 Moscow, RussiaDepartment of Chemistry, Lomonosov Moscow State University, Leninskie Gory 1, 119991 Moscow, RussiaDepartment of Chemistry, Lomonosov Moscow State University, Leninskie Gory 1, 119991 Moscow, RussiaIn 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.https://www.mdpi.com/2079-6382/10/5/489chloramphenicolalkyl(triphenyl)phosphoniumbacterial ribosomemolecular dynamics simulationsantibiotic activityantiproliferative activity |