Cargando…

Ursolic acid inhibits colistin efflux and curtails colistin resistant Enterobacteriaceae

Colistin resistance in Enterobacteriaceae especially Klebsiella pneumoniae and Escherichia coli is driving the evolution of pan drug resistant strains. Screening a library of 13 plant nutraceuticals led to the identification of acetyl shikonin and ursolic acid, which exhibited synergy with colistin...

Descripción completa

Detalles Bibliográficos
Autores principales: Sundaramoorthy, Niranjana Sri, Mohan, Harihar M., Subramaniam, Shankar, Raman, Thiagarajan, Selva Ganesan, Subramaniapillai, Sivasubamanian, Aravind, Nagarajan, Saisubramanian
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer Berlin Heidelberg 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6379497/
https://www.ncbi.nlm.nih.gov/pubmed/30778773
http://dx.doi.org/10.1186/s13568-019-0750-4
_version_ 1783396100604952576
author Sundaramoorthy, Niranjana Sri
Mohan, Harihar M.
Subramaniam, Shankar
Raman, Thiagarajan
Selva Ganesan, Subramaniapillai
Sivasubamanian, Aravind
Nagarajan, Saisubramanian
author_facet Sundaramoorthy, Niranjana Sri
Mohan, Harihar M.
Subramaniam, Shankar
Raman, Thiagarajan
Selva Ganesan, Subramaniapillai
Sivasubamanian, Aravind
Nagarajan, Saisubramanian
author_sort Sundaramoorthy, Niranjana Sri
collection PubMed
description Colistin resistance in Enterobacteriaceae especially Klebsiella pneumoniae and Escherichia coli is driving the evolution of pan drug resistant strains. Screening a library of 13 plant nutraceuticals led to the identification of acetyl shikonin and ursolic acid, which exhibited synergy with colistin against extremely drug resistant (XDR) clinical strains of E. coli (U3790) and K. pneumoniae (BC936). Ursolic acid caused a significant colistin MIC reversal of 16-fold in U3790 and 4-fold in BC936 strains. Ursolic acid also potentiated the bactericidal effect of colistin against both U3790 and BC936 by causing ~ 4 to 4.5 log fold decline in CFU of both clinical isolates in a time kill assay. At 2× minimum effective concentration, ursolic acid was non-toxic to zebrafish as evidenced by brain and liver enzyme profiles and by histopathology studies. In combination with colistin, ursolic acid reduced bacterial bioburden of U3790/BC936 by 1–1.58 log fold from the infected muscle tissue of zebrafish. Mechanistic explorations via studies on real time efflux, membrane potential and intracellular accumulation of dansyl chloride tagged colistin revealed that colistin efflux is inhibited by ursolic acid. In addition, ursolic acid also enhanced outer membrane permeability which probably facilitates colistin’s attack on outer and inner membranes. Our study shows that ursolic acid synergizes with colistin by inhibiting colistin efflux in Enterobacteriaceae that helps to curtail colistin resistant Enterobacteriaceae. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s13568-019-0750-4) contains supplementary material, which is available to authorized users.
format Online
Article
Text
id pubmed-6379497
institution National Center for Biotechnology Information
language English
publishDate 2019
publisher Springer Berlin Heidelberg
record_format MEDLINE/PubMed
spelling pubmed-63794972019-03-10 Ursolic acid inhibits colistin efflux and curtails colistin resistant Enterobacteriaceae Sundaramoorthy, Niranjana Sri Mohan, Harihar M. Subramaniam, Shankar Raman, Thiagarajan Selva Ganesan, Subramaniapillai Sivasubamanian, Aravind Nagarajan, Saisubramanian AMB Express Original Article Colistin resistance in Enterobacteriaceae especially Klebsiella pneumoniae and Escherichia coli is driving the evolution of pan drug resistant strains. Screening a library of 13 plant nutraceuticals led to the identification of acetyl shikonin and ursolic acid, which exhibited synergy with colistin against extremely drug resistant (XDR) clinical strains of E. coli (U3790) and K. pneumoniae (BC936). Ursolic acid caused a significant colistin MIC reversal of 16-fold in U3790 and 4-fold in BC936 strains. Ursolic acid also potentiated the bactericidal effect of colistin against both U3790 and BC936 by causing ~ 4 to 4.5 log fold decline in CFU of both clinical isolates in a time kill assay. At 2× minimum effective concentration, ursolic acid was non-toxic to zebrafish as evidenced by brain and liver enzyme profiles and by histopathology studies. In combination with colistin, ursolic acid reduced bacterial bioburden of U3790/BC936 by 1–1.58 log fold from the infected muscle tissue of zebrafish. Mechanistic explorations via studies on real time efflux, membrane potential and intracellular accumulation of dansyl chloride tagged colistin revealed that colistin efflux is inhibited by ursolic acid. In addition, ursolic acid also enhanced outer membrane permeability which probably facilitates colistin’s attack on outer and inner membranes. Our study shows that ursolic acid synergizes with colistin by inhibiting colistin efflux in Enterobacteriaceae that helps to curtail colistin resistant Enterobacteriaceae. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s13568-019-0750-4) contains supplementary material, which is available to authorized users. Springer Berlin Heidelberg 2019-02-18 /pmc/articles/PMC6379497/ /pubmed/30778773 http://dx.doi.org/10.1186/s13568-019-0750-4 Text en © The Author(s) 2019 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
spellingShingle Original Article
Sundaramoorthy, Niranjana Sri
Mohan, Harihar M.
Subramaniam, Shankar
Raman, Thiagarajan
Selva Ganesan, Subramaniapillai
Sivasubamanian, Aravind
Nagarajan, Saisubramanian
Ursolic acid inhibits colistin efflux and curtails colistin resistant Enterobacteriaceae
title Ursolic acid inhibits colistin efflux and curtails colistin resistant Enterobacteriaceae
title_full Ursolic acid inhibits colistin efflux and curtails colistin resistant Enterobacteriaceae
title_fullStr Ursolic acid inhibits colistin efflux and curtails colistin resistant Enterobacteriaceae
title_full_unstemmed Ursolic acid inhibits colistin efflux and curtails colistin resistant Enterobacteriaceae
title_short Ursolic acid inhibits colistin efflux and curtails colistin resistant Enterobacteriaceae
title_sort ursolic acid inhibits colistin efflux and curtails colistin resistant enterobacteriaceae
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6379497/
https://www.ncbi.nlm.nih.gov/pubmed/30778773
http://dx.doi.org/10.1186/s13568-019-0750-4
work_keys_str_mv AT sundaramoorthyniranjanasri ursolicacidinhibitscolistineffluxandcurtailscolistinresistantenterobacteriaceae
AT mohanhariharm ursolicacidinhibitscolistineffluxandcurtailscolistinresistantenterobacteriaceae
AT subramaniamshankar ursolicacidinhibitscolistineffluxandcurtailscolistinresistantenterobacteriaceae
AT ramanthiagarajan ursolicacidinhibitscolistineffluxandcurtailscolistinresistantenterobacteriaceae
AT selvaganesansubramaniapillai ursolicacidinhibitscolistineffluxandcurtailscolistinresistantenterobacteriaceae
AT sivasubamanianaravind ursolicacidinhibitscolistineffluxandcurtailscolistinresistantenterobacteriaceae
AT nagarajansaisubramanian ursolicacidinhibitscolistineffluxandcurtailscolistinresistantenterobacteriaceae