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Design, Synthesis and Biological Evaluation of 1-Phenyl-2-(phenylamino) Ethanone Derivatives as Novel MCR-1 Inhibitors

Polymyxins are considered to be the last-line antibiotics that are used to treat infections caused by multidrug-resistant (MDR) gram-negative bacteria; however, the plasmid-mediated transferable colistin resistance gene (mcr-1) has rendered polymyxins ineffective. Therefore, the protein encoded by m...

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Autores principales: Lan, Xiu-juan, Yan, Hai-tao, Lin, Feng, Hou, Shi, Li, Chen-chen, Wang, Guang-shu, Sun, Wei, Xiao, Jun-hai, Li, Song
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6696459/
https://www.ncbi.nlm.nih.gov/pubmed/31357453
http://dx.doi.org/10.3390/molecules24152719
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author Lan, Xiu-juan
Yan, Hai-tao
Lin, Feng
Hou, Shi
Li, Chen-chen
Wang, Guang-shu
Sun, Wei
Xiao, Jun-hai
Li, Song
author_facet Lan, Xiu-juan
Yan, Hai-tao
Lin, Feng
Hou, Shi
Li, Chen-chen
Wang, Guang-shu
Sun, Wei
Xiao, Jun-hai
Li, Song
author_sort Lan, Xiu-juan
collection PubMed
description Polymyxins are considered to be the last-line antibiotics that are used to treat infections caused by multidrug-resistant (MDR) gram-negative bacteria; however, the plasmid-mediated transferable colistin resistance gene (mcr-1) has rendered polymyxins ineffective. Therefore, the protein encoded by mcr-1, MCR-1, could be a target for structure-based design of inhibitors to tackle polymyxins resistance. Here, we identified racemic compound 3 as a potential MCR-1 inhibitor by virtual screening, and 26 compound 3 derivatives were synthesized and evaluated in vitro. In the cell-based assay, compound 6g, 6h, 6i, 6n, 6p, 6q, and 6r displayed more potent activity than compound 3. Notably, 25 μΜ of compound 6p or 6q combined with 2 μg·mL-1 colistin could completely inhibit the growth of BL21(DE3) expressing mcr-1, which exhibited the most potent activity. In the enzymatic assay, we elucidate that 6p and 6q could target the MCR-1 to inhibit the activity of the protein. Additionally, a molecular docking study showed that 6p and 6q could interact with Glu246 and Thr285 via hydrogen bonds and occupy well the cavity of the MCR-1 protein. These results may provide a potential avenue to overcome colistin resistance, and provide some valuable information for further investigation on MCR-1 inhibitors.
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spelling pubmed-66964592019-09-05 Design, Synthesis and Biological Evaluation of 1-Phenyl-2-(phenylamino) Ethanone Derivatives as Novel MCR-1 Inhibitors Lan, Xiu-juan Yan, Hai-tao Lin, Feng Hou, Shi Li, Chen-chen Wang, Guang-shu Sun, Wei Xiao, Jun-hai Li, Song Molecules Article Polymyxins are considered to be the last-line antibiotics that are used to treat infections caused by multidrug-resistant (MDR) gram-negative bacteria; however, the plasmid-mediated transferable colistin resistance gene (mcr-1) has rendered polymyxins ineffective. Therefore, the protein encoded by mcr-1, MCR-1, could be a target for structure-based design of inhibitors to tackle polymyxins resistance. Here, we identified racemic compound 3 as a potential MCR-1 inhibitor by virtual screening, and 26 compound 3 derivatives were synthesized and evaluated in vitro. In the cell-based assay, compound 6g, 6h, 6i, 6n, 6p, 6q, and 6r displayed more potent activity than compound 3. Notably, 25 μΜ of compound 6p or 6q combined with 2 μg·mL-1 colistin could completely inhibit the growth of BL21(DE3) expressing mcr-1, which exhibited the most potent activity. In the enzymatic assay, we elucidate that 6p and 6q could target the MCR-1 to inhibit the activity of the protein. Additionally, a molecular docking study showed that 6p and 6q could interact with Glu246 and Thr285 via hydrogen bonds and occupy well the cavity of the MCR-1 protein. These results may provide a potential avenue to overcome colistin resistance, and provide some valuable information for further investigation on MCR-1 inhibitors. MDPI 2019-07-26 /pmc/articles/PMC6696459/ /pubmed/31357453 http://dx.doi.org/10.3390/molecules24152719 Text en © 2019 by the authors. 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 (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Lan, Xiu-juan
Yan, Hai-tao
Lin, Feng
Hou, Shi
Li, Chen-chen
Wang, Guang-shu
Sun, Wei
Xiao, Jun-hai
Li, Song
Design, Synthesis and Biological Evaluation of 1-Phenyl-2-(phenylamino) Ethanone Derivatives as Novel MCR-1 Inhibitors
title Design, Synthesis and Biological Evaluation of 1-Phenyl-2-(phenylamino) Ethanone Derivatives as Novel MCR-1 Inhibitors
title_full Design, Synthesis and Biological Evaluation of 1-Phenyl-2-(phenylamino) Ethanone Derivatives as Novel MCR-1 Inhibitors
title_fullStr Design, Synthesis and Biological Evaluation of 1-Phenyl-2-(phenylamino) Ethanone Derivatives as Novel MCR-1 Inhibitors
title_full_unstemmed Design, Synthesis and Biological Evaluation of 1-Phenyl-2-(phenylamino) Ethanone Derivatives as Novel MCR-1 Inhibitors
title_short Design, Synthesis and Biological Evaluation of 1-Phenyl-2-(phenylamino) Ethanone Derivatives as Novel MCR-1 Inhibitors
title_sort design, synthesis and biological evaluation of 1-phenyl-2-(phenylamino) ethanone derivatives as novel mcr-1 inhibitors
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6696459/
https://www.ncbi.nlm.nih.gov/pubmed/31357453
http://dx.doi.org/10.3390/molecules24152719
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