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A Novel Actin Binding Drug with In Vivo Efficacy
Occidiofungin is produced by the soil bacterium Burkolderia contaminans MS14 and is structurally similar or identical to the burkholdines, xylocandins, and cepacidines. This study identified the primary cellular target of occidiofungin, which was determined to be actin. The modification of occidiofu...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Society for Microbiology
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6325233/ https://www.ncbi.nlm.nih.gov/pubmed/30323040 http://dx.doi.org/10.1128/AAC.01585-18 |
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author | Ravichandran, Akshaya Geng, Mengxin Hull, Kenneth G. Li, Jing Romo, Daniel Lu, Shi-En Albee, Aaron Nutter, Christopher Gordon, Donna M. Ghannoum, Mahmoud A. Lockless, Steve W. Smith, Leif |
author_facet | Ravichandran, Akshaya Geng, Mengxin Hull, Kenneth G. Li, Jing Romo, Daniel Lu, Shi-En Albee, Aaron Nutter, Christopher Gordon, Donna M. Ghannoum, Mahmoud A. Lockless, Steve W. Smith, Leif |
author_sort | Ravichandran, Akshaya |
collection | PubMed |
description | Occidiofungin is produced by the soil bacterium Burkolderia contaminans MS14 and is structurally similar or identical to the burkholdines, xylocandins, and cepacidines. This study identified the primary cellular target of occidiofungin, which was determined to be actin. The modification of occidiofungin with a functional alkyne group enabled affinity purification assays and localization studies in yeast. Occidiofungin has a subtle effect on actin dynamics that triggers apoptotic cell death. We demonstrate the highly specific localization of occidiofungin to cellular regions rich in actin in yeast and the binding of occidiofungin to purified actin in vitro. Furthermore, a disruption of actin-mediated cellular processes, such as endocytosis, nuclear segregation, and hyphal formation, was observed. All of these processes require the formation of stable actin cables, which are disrupted following the addition of a subinhibitory concentration of occidiofungin. We were also able to demonstrate the effectiveness of occidiofungin in treating a vulvovaginal yeast infection in a murine model. The results of this study are important for the development of an efficacious novel class of actin binding drugs that may fill the existing gap in treatment options for fungal infections or different types of cancer. |
format | Online Article Text |
id | pubmed-6325233 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | American Society for Microbiology |
record_format | MEDLINE/PubMed |
spelling | pubmed-63252332019-02-01 A Novel Actin Binding Drug with In Vivo Efficacy Ravichandran, Akshaya Geng, Mengxin Hull, Kenneth G. Li, Jing Romo, Daniel Lu, Shi-En Albee, Aaron Nutter, Christopher Gordon, Donna M. Ghannoum, Mahmoud A. Lockless, Steve W. Smith, Leif Antimicrob Agents Chemother Mechanisms of Action: Physiological Effects Occidiofungin is produced by the soil bacterium Burkolderia contaminans MS14 and is structurally similar or identical to the burkholdines, xylocandins, and cepacidines. This study identified the primary cellular target of occidiofungin, which was determined to be actin. The modification of occidiofungin with a functional alkyne group enabled affinity purification assays and localization studies in yeast. Occidiofungin has a subtle effect on actin dynamics that triggers apoptotic cell death. We demonstrate the highly specific localization of occidiofungin to cellular regions rich in actin in yeast and the binding of occidiofungin to purified actin in vitro. Furthermore, a disruption of actin-mediated cellular processes, such as endocytosis, nuclear segregation, and hyphal formation, was observed. All of these processes require the formation of stable actin cables, which are disrupted following the addition of a subinhibitory concentration of occidiofungin. We were also able to demonstrate the effectiveness of occidiofungin in treating a vulvovaginal yeast infection in a murine model. The results of this study are important for the development of an efficacious novel class of actin binding drugs that may fill the existing gap in treatment options for fungal infections or different types of cancer. American Society for Microbiology 2018-12-21 /pmc/articles/PMC6325233/ /pubmed/30323040 http://dx.doi.org/10.1128/AAC.01585-18 Text en Copyright © 2018 Ravichandran et al. https://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Mechanisms of Action: Physiological Effects Ravichandran, Akshaya Geng, Mengxin Hull, Kenneth G. Li, Jing Romo, Daniel Lu, Shi-En Albee, Aaron Nutter, Christopher Gordon, Donna M. Ghannoum, Mahmoud A. Lockless, Steve W. Smith, Leif A Novel Actin Binding Drug with In Vivo Efficacy |
title | A Novel Actin Binding Drug with In Vivo Efficacy |
title_full | A Novel Actin Binding Drug with In Vivo Efficacy |
title_fullStr | A Novel Actin Binding Drug with In Vivo Efficacy |
title_full_unstemmed | A Novel Actin Binding Drug with In Vivo Efficacy |
title_short | A Novel Actin Binding Drug with In Vivo Efficacy |
title_sort | novel actin binding drug with in vivo efficacy |
topic | Mechanisms of Action: Physiological Effects |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6325233/ https://www.ncbi.nlm.nih.gov/pubmed/30323040 http://dx.doi.org/10.1128/AAC.01585-18 |
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