Fluopsin C for Treating Multidrug-Resistant Infections: In vitro Activity Against Clinically Important Strains and in vivo Efficacy Against Carbapenemase-Producing Klebsiella pneumoniae
The increasing emergence of multidrug-resistant (MDR) organisms in hospital infections is causing a global public health crisis. The development of drugs with effective antibiotic action against such agents is of the highest priority. In the present study, the action of Fluopsin C against MDR clinic...
Autores principales: | , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Frontiers Media S.A.
2019
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6824035/ https://www.ncbi.nlm.nih.gov/pubmed/31708901 http://dx.doi.org/10.3389/fmicb.2019.02431 |
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author | Navarro, Miguel Octavio Pérez Simionato, Ane Stefano Pérez, Juan Carlos Bedoya Barazetti, André Riedi Emiliano, Janaina Niekawa, Erika Tyemi Goya Andreata, Matheus Felipe de Lima Modolon, Fluvio Dealis, Mickely Liuti Araújo, Eduardo José de Almeida Carlos, Thalita Massi Scarpelim, Odair José da Silva, Denise Brentan Chryssafidis, Andreas Lazaros Bruheim, Per Andrade, Galdino |
author_facet | Navarro, Miguel Octavio Pérez Simionato, Ane Stefano Pérez, Juan Carlos Bedoya Barazetti, André Riedi Emiliano, Janaina Niekawa, Erika Tyemi Goya Andreata, Matheus Felipe de Lima Modolon, Fluvio Dealis, Mickely Liuti Araújo, Eduardo José de Almeida Carlos, Thalita Massi Scarpelim, Odair José da Silva, Denise Brentan Chryssafidis, Andreas Lazaros Bruheim, Per Andrade, Galdino |
author_sort | Navarro, Miguel Octavio Pérez |
collection | PubMed |
description | The increasing emergence of multidrug-resistant (MDR) organisms in hospital infections is causing a global public health crisis. The development of drugs with effective antibiotic action against such agents is of the highest priority. In the present study, the action of Fluopsin C against MDR clinical isolates was evaluated under in vitro and in vivo conditions. Fluopsin C was produced in cell suspension culture of Pseudomonas aeruginosa LV strain, purified by liquid adsorption chromatography and identified by mass spectrometric analysis. Bioactivity, bacterial resistance development risk against clinically important pathogenic strains and toxicity in mammalian cell were initially determined by in vitro models. In vivo toxicity was evaluated in Tenebrio molitor larvae and mice. The therapeutic efficacy of intravenous Fluopsin C administration was evaluated in a murine model of Klebsiella pneumoniae (KPC) acute sepsis, using six different treatments. The in vitro results indicated MIC and MBC below 2 μg/mL and low bacterial resistance development frequency. Electron microscopy showed that Fluopsin C may have altered the exopolysaccharide matrix and caused disruption of the cell wall of MDR bacteria. Best therapeutic results were achieved in mice treated with a single dose of 2 mg/kg and in mice treated with two doses of 1 mg/kg, 8 h apart. Furthermore, acute and chronic histopathological studies demonstrated absent nephrotoxicity and moderate hepatotoxicity. The results demonstrated the efficacy of Fluopsin C against MDR organisms in in vitro and in vivo models, and hence it can be a novel therapeutic agent for the control of severe MDR infections. |
format | Online Article Text |
id | pubmed-6824035 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-68240352019-11-08 Fluopsin C for Treating Multidrug-Resistant Infections: In vitro Activity Against Clinically Important Strains and in vivo Efficacy Against Carbapenemase-Producing Klebsiella pneumoniae Navarro, Miguel Octavio Pérez Simionato, Ane Stefano Pérez, Juan Carlos Bedoya Barazetti, André Riedi Emiliano, Janaina Niekawa, Erika Tyemi Goya Andreata, Matheus Felipe de Lima Modolon, Fluvio Dealis, Mickely Liuti Araújo, Eduardo José de Almeida Carlos, Thalita Massi Scarpelim, Odair José da Silva, Denise Brentan Chryssafidis, Andreas Lazaros Bruheim, Per Andrade, Galdino Front Microbiol Microbiology The increasing emergence of multidrug-resistant (MDR) organisms in hospital infections is causing a global public health crisis. The development of drugs with effective antibiotic action against such agents is of the highest priority. In the present study, the action of Fluopsin C against MDR clinical isolates was evaluated under in vitro and in vivo conditions. Fluopsin C was produced in cell suspension culture of Pseudomonas aeruginosa LV strain, purified by liquid adsorption chromatography and identified by mass spectrometric analysis. Bioactivity, bacterial resistance development risk against clinically important pathogenic strains and toxicity in mammalian cell were initially determined by in vitro models. In vivo toxicity was evaluated in Tenebrio molitor larvae and mice. The therapeutic efficacy of intravenous Fluopsin C administration was evaluated in a murine model of Klebsiella pneumoniae (KPC) acute sepsis, using six different treatments. The in vitro results indicated MIC and MBC below 2 μg/mL and low bacterial resistance development frequency. Electron microscopy showed that Fluopsin C may have altered the exopolysaccharide matrix and caused disruption of the cell wall of MDR bacteria. Best therapeutic results were achieved in mice treated with a single dose of 2 mg/kg and in mice treated with two doses of 1 mg/kg, 8 h apart. Furthermore, acute and chronic histopathological studies demonstrated absent nephrotoxicity and moderate hepatotoxicity. The results demonstrated the efficacy of Fluopsin C against MDR organisms in in vitro and in vivo models, and hence it can be a novel therapeutic agent for the control of severe MDR infections. Frontiers Media S.A. 2019-10-25 /pmc/articles/PMC6824035/ /pubmed/31708901 http://dx.doi.org/10.3389/fmicb.2019.02431 Text en Copyright © 2019 Navarro, Simionato, Pérez, Barazetti, Emiliano, Niekawa, Andreata, Modolon, Dealis, Araújo, Carlos, Scarpelim, da Silva, Chryssafidis, Bruheim and Andrade. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Microbiology Navarro, Miguel Octavio Pérez Simionato, Ane Stefano Pérez, Juan Carlos Bedoya Barazetti, André Riedi Emiliano, Janaina Niekawa, Erika Tyemi Goya Andreata, Matheus Felipe de Lima Modolon, Fluvio Dealis, Mickely Liuti Araújo, Eduardo José de Almeida Carlos, Thalita Massi Scarpelim, Odair José da Silva, Denise Brentan Chryssafidis, Andreas Lazaros Bruheim, Per Andrade, Galdino Fluopsin C for Treating Multidrug-Resistant Infections: In vitro Activity Against Clinically Important Strains and in vivo Efficacy Against Carbapenemase-Producing Klebsiella pneumoniae |
title | Fluopsin C for Treating Multidrug-Resistant Infections: In vitro Activity Against Clinically Important Strains and in vivo Efficacy Against Carbapenemase-Producing Klebsiella pneumoniae |
title_full | Fluopsin C for Treating Multidrug-Resistant Infections: In vitro Activity Against Clinically Important Strains and in vivo Efficacy Against Carbapenemase-Producing Klebsiella pneumoniae |
title_fullStr | Fluopsin C for Treating Multidrug-Resistant Infections: In vitro Activity Against Clinically Important Strains and in vivo Efficacy Against Carbapenemase-Producing Klebsiella pneumoniae |
title_full_unstemmed | Fluopsin C for Treating Multidrug-Resistant Infections: In vitro Activity Against Clinically Important Strains and in vivo Efficacy Against Carbapenemase-Producing Klebsiella pneumoniae |
title_short | Fluopsin C for Treating Multidrug-Resistant Infections: In vitro Activity Against Clinically Important Strains and in vivo Efficacy Against Carbapenemase-Producing Klebsiella pneumoniae |
title_sort | fluopsin c for treating multidrug-resistant infections: in vitro activity against clinically important strains and in vivo efficacy against carbapenemase-producing klebsiella pneumoniae |
topic | Microbiology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6824035/ https://www.ncbi.nlm.nih.gov/pubmed/31708901 http://dx.doi.org/10.3389/fmicb.2019.02431 |
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