Cargando…

Pogostone Enhances the Antibacterial Activity of Colistin against MCR-1-Positive Bacteria by Inhibiting the Biological Function of MCR-1

The emergence of the plasmid-mediated colistin resistance gene mcr-1 has resulted in the loss of available treatments for certain severe infections. Here we identified a potential inhibitor of MCR-1 for the treatment of infections caused by MCR-1-positive drug-resistant bacteria, especially MCR-1-po...

Descripción completa

Detalles Bibliográficos
Autores principales: Xie, Shengnan, Li, Li, Zhan, Baihe, Shen, Xue, Deng, Xuming, Tan, Wenxi, Fang, Tianqi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9102576/
https://www.ncbi.nlm.nih.gov/pubmed/35566163
http://dx.doi.org/10.3390/molecules27092819
_version_ 1784707361742520320
author Xie, Shengnan
Li, Li
Zhan, Baihe
Shen, Xue
Deng, Xuming
Tan, Wenxi
Fang, Tianqi
author_facet Xie, Shengnan
Li, Li
Zhan, Baihe
Shen, Xue
Deng, Xuming
Tan, Wenxi
Fang, Tianqi
author_sort Xie, Shengnan
collection PubMed
description The emergence of the plasmid-mediated colistin resistance gene mcr-1 has resulted in the loss of available treatments for certain severe infections. Here we identified a potential inhibitor of MCR-1 for the treatment of infections caused by MCR-1-positive drug-resistant bacteria, especially MCR-1-positive carbapenem-resistant Enterobacteriaceae (CRE). A checkerboard minimum inhibitory concentration (MIC) test, a killing curve test, a growth curve test, bacterial live/dead assays, scanning electron microscope (SEM) analysis, cytotoxicity tests, molecular dynamics simulation analysis, and animal studies were used to confirm the in vivo/in vitro synergistic effects of pogostone and colistin. The results showed that pogostone could restore the bactericidal activity of colistin against all tested MCR-1-positive bacterial strains or MCR-1 mutant–positive bacterial strains (FIC < 0.5). Pogostone does not inhibit the expression of MCR-1. Rather, it inhibits the binding of MCR-1 to substrates by binding to amino acids in the active region of MCR-1, thus inhibiting the biological activity of MCR-1 and its mutants (such as MCR-3). An in vivo mouse systemic infection model, pogostone in combination with colistin resulted in 80.0% (the survival rates after monotherapy with colistin or pogostone alone were 33.3% and 40.0%) survival at 72 h after infection of MCR-1-positve Escherichia coli (E. coli) ZJ487 (blaNDM-1-carrying), and pogostone in combination with colistin led to one or more order of magnitude decreases in the bacterial burdens in the liver, spleen and kidney compared with pogostone or colistin alone. Our results confirm that pogostone is a potential inhibitor of MCR-1 for use in combination with polymyxin for the treatment of severe infections caused by MCR-1-positive Enterobacteriaceae.
format Online
Article
Text
id pubmed-9102576
institution National Center for Biotechnology Information
language English
publishDate 2022
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-91025762022-05-14 Pogostone Enhances the Antibacterial Activity of Colistin against MCR-1-Positive Bacteria by Inhibiting the Biological Function of MCR-1 Xie, Shengnan Li, Li Zhan, Baihe Shen, Xue Deng, Xuming Tan, Wenxi Fang, Tianqi Molecules Article The emergence of the plasmid-mediated colistin resistance gene mcr-1 has resulted in the loss of available treatments for certain severe infections. Here we identified a potential inhibitor of MCR-1 for the treatment of infections caused by MCR-1-positive drug-resistant bacteria, especially MCR-1-positive carbapenem-resistant Enterobacteriaceae (CRE). A checkerboard minimum inhibitory concentration (MIC) test, a killing curve test, a growth curve test, bacterial live/dead assays, scanning electron microscope (SEM) analysis, cytotoxicity tests, molecular dynamics simulation analysis, and animal studies were used to confirm the in vivo/in vitro synergistic effects of pogostone and colistin. The results showed that pogostone could restore the bactericidal activity of colistin against all tested MCR-1-positive bacterial strains or MCR-1 mutant–positive bacterial strains (FIC < 0.5). Pogostone does not inhibit the expression of MCR-1. Rather, it inhibits the binding of MCR-1 to substrates by binding to amino acids in the active region of MCR-1, thus inhibiting the biological activity of MCR-1 and its mutants (such as MCR-3). An in vivo mouse systemic infection model, pogostone in combination with colistin resulted in 80.0% (the survival rates after monotherapy with colistin or pogostone alone were 33.3% and 40.0%) survival at 72 h after infection of MCR-1-positve Escherichia coli (E. coli) ZJ487 (blaNDM-1-carrying), and pogostone in combination with colistin led to one or more order of magnitude decreases in the bacterial burdens in the liver, spleen and kidney compared with pogostone or colistin alone. Our results confirm that pogostone is a potential inhibitor of MCR-1 for use in combination with polymyxin for the treatment of severe infections caused by MCR-1-positive Enterobacteriaceae. MDPI 2022-04-28 /pmc/articles/PMC9102576/ /pubmed/35566163 http://dx.doi.org/10.3390/molecules27092819 Text en © 2022 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
Xie, Shengnan
Li, Li
Zhan, Baihe
Shen, Xue
Deng, Xuming
Tan, Wenxi
Fang, Tianqi
Pogostone Enhances the Antibacterial Activity of Colistin against MCR-1-Positive Bacteria by Inhibiting the Biological Function of MCR-1
title Pogostone Enhances the Antibacterial Activity of Colistin against MCR-1-Positive Bacteria by Inhibiting the Biological Function of MCR-1
title_full Pogostone Enhances the Antibacterial Activity of Colistin against MCR-1-Positive Bacteria by Inhibiting the Biological Function of MCR-1
title_fullStr Pogostone Enhances the Antibacterial Activity of Colistin against MCR-1-Positive Bacteria by Inhibiting the Biological Function of MCR-1
title_full_unstemmed Pogostone Enhances the Antibacterial Activity of Colistin against MCR-1-Positive Bacteria by Inhibiting the Biological Function of MCR-1
title_short Pogostone Enhances the Antibacterial Activity of Colistin against MCR-1-Positive Bacteria by Inhibiting the Biological Function of MCR-1
title_sort pogostone enhances the antibacterial activity of colistin against mcr-1-positive bacteria by inhibiting the biological function of mcr-1
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9102576/
https://www.ncbi.nlm.nih.gov/pubmed/35566163
http://dx.doi.org/10.3390/molecules27092819
work_keys_str_mv AT xieshengnan pogostoneenhancestheantibacterialactivityofcolistinagainstmcr1positivebacteriabyinhibitingthebiologicalfunctionofmcr1
AT lili pogostoneenhancestheantibacterialactivityofcolistinagainstmcr1positivebacteriabyinhibitingthebiologicalfunctionofmcr1
AT zhanbaihe pogostoneenhancestheantibacterialactivityofcolistinagainstmcr1positivebacteriabyinhibitingthebiologicalfunctionofmcr1
AT shenxue pogostoneenhancestheantibacterialactivityofcolistinagainstmcr1positivebacteriabyinhibitingthebiologicalfunctionofmcr1
AT dengxuming pogostoneenhancestheantibacterialactivityofcolistinagainstmcr1positivebacteriabyinhibitingthebiologicalfunctionofmcr1
AT tanwenxi pogostoneenhancestheantibacterialactivityofcolistinagainstmcr1positivebacteriabyinhibitingthebiologicalfunctionofmcr1
AT fangtianqi pogostoneenhancestheantibacterialactivityofcolistinagainstmcr1positivebacteriabyinhibitingthebiologicalfunctionofmcr1