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Facile accelerated specific therapeutic (FAST) platform develops antisense therapies to counter multidrug-resistant bacteria
Multidrug-resistant (MDR) bacteria pose a grave concern to global health, which is perpetuated by a lack of new treatments and countermeasure platforms to combat outbreaks or antibiotic resistance. To address this, we have developed a Facile Accelerated Specific Therapeutic (FAST) platform that can...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Nature Publishing Group UK
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7955031/ https://www.ncbi.nlm.nih.gov/pubmed/33712689 http://dx.doi.org/10.1038/s42003-021-01856-1 |
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author | Eller, Kristen A. Aunins, Thomas R. Courtney, Colleen M. Campos, Jocelyn K. Otoupal, Peter B. Erickson, Keesha E. Madinger, Nancy E. Chatterjee, Anushree |
author_facet | Eller, Kristen A. Aunins, Thomas R. Courtney, Colleen M. Campos, Jocelyn K. Otoupal, Peter B. Erickson, Keesha E. Madinger, Nancy E. Chatterjee, Anushree |
author_sort | Eller, Kristen A. |
collection | PubMed |
description | Multidrug-resistant (MDR) bacteria pose a grave concern to global health, which is perpetuated by a lack of new treatments and countermeasure platforms to combat outbreaks or antibiotic resistance. To address this, we have developed a Facile Accelerated Specific Therapeutic (FAST) platform that can develop effective peptide nucleic acid (PNA) therapies against MDR bacteria within a week. Our FAST platform uses a bioinformatics toolbox to design sequence-specific PNAs targeting non-traditional pathways/genes of bacteria, then performs in-situ synthesis, validation, and efficacy testing of selected PNAs. As a proof of concept, these PNAs were tested against five MDR clinical isolates: carbapenem-resistant Escherichia coli, extended-spectrum beta-lactamase Klebsiella pneumoniae, New Delhi Metallo-beta-lactamase-1 carrying Klebsiella pneumoniae, and MDR Salmonella enterica. PNAs showed significant growth inhibition for 82% of treatments, with nearly 18% of treatments leading to greater than 97% decrease. Further, these PNAs are capable of potentiating antibiotic activity in the clinical isolates despite presence of cognate resistance genes. Finally, the FAST platform offers a novel delivery approach to overcome limited transport of PNAs into mammalian cells by repurposing the bacterial Type III secretion system in conjunction with a kill switch that is effective at eliminating 99.6% of an intracellular Salmonella infection in human epithelial cells. |
format | Online Article Text |
id | pubmed-7955031 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-79550312021-03-28 Facile accelerated specific therapeutic (FAST) platform develops antisense therapies to counter multidrug-resistant bacteria Eller, Kristen A. Aunins, Thomas R. Courtney, Colleen M. Campos, Jocelyn K. Otoupal, Peter B. Erickson, Keesha E. Madinger, Nancy E. Chatterjee, Anushree Commun Biol Article Multidrug-resistant (MDR) bacteria pose a grave concern to global health, which is perpetuated by a lack of new treatments and countermeasure platforms to combat outbreaks or antibiotic resistance. To address this, we have developed a Facile Accelerated Specific Therapeutic (FAST) platform that can develop effective peptide nucleic acid (PNA) therapies against MDR bacteria within a week. Our FAST platform uses a bioinformatics toolbox to design sequence-specific PNAs targeting non-traditional pathways/genes of bacteria, then performs in-situ synthesis, validation, and efficacy testing of selected PNAs. As a proof of concept, these PNAs were tested against five MDR clinical isolates: carbapenem-resistant Escherichia coli, extended-spectrum beta-lactamase Klebsiella pneumoniae, New Delhi Metallo-beta-lactamase-1 carrying Klebsiella pneumoniae, and MDR Salmonella enterica. PNAs showed significant growth inhibition for 82% of treatments, with nearly 18% of treatments leading to greater than 97% decrease. Further, these PNAs are capable of potentiating antibiotic activity in the clinical isolates despite presence of cognate resistance genes. Finally, the FAST platform offers a novel delivery approach to overcome limited transport of PNAs into mammalian cells by repurposing the bacterial Type III secretion system in conjunction with a kill switch that is effective at eliminating 99.6% of an intracellular Salmonella infection in human epithelial cells. Nature Publishing Group UK 2021-03-12 /pmc/articles/PMC7955031/ /pubmed/33712689 http://dx.doi.org/10.1038/s42003-021-01856-1 Text en © The Author(s) 2021 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as 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. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Eller, Kristen A. Aunins, Thomas R. Courtney, Colleen M. Campos, Jocelyn K. Otoupal, Peter B. Erickson, Keesha E. Madinger, Nancy E. Chatterjee, Anushree Facile accelerated specific therapeutic (FAST) platform develops antisense therapies to counter multidrug-resistant bacteria |
title | Facile accelerated specific therapeutic (FAST) platform develops antisense therapies to counter multidrug-resistant bacteria |
title_full | Facile accelerated specific therapeutic (FAST) platform develops antisense therapies to counter multidrug-resistant bacteria |
title_fullStr | Facile accelerated specific therapeutic (FAST) platform develops antisense therapies to counter multidrug-resistant bacteria |
title_full_unstemmed | Facile accelerated specific therapeutic (FAST) platform develops antisense therapies to counter multidrug-resistant bacteria |
title_short | Facile accelerated specific therapeutic (FAST) platform develops antisense therapies to counter multidrug-resistant bacteria |
title_sort | facile accelerated specific therapeutic (fast) platform develops antisense therapies to counter multidrug-resistant bacteria |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7955031/ https://www.ncbi.nlm.nih.gov/pubmed/33712689 http://dx.doi.org/10.1038/s42003-021-01856-1 |
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