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Identifying Metabolic Inhibitors to Reduce Bacterial Persistence
Bacterial persisters are rare phenotypic variants that are temporarily tolerant to high concentrations of antibiotics. We have previously discovered that stationary-phase-cell subpopulations exhibiting high redox activities were less capable of producing proteins and resuming growth upon their dilut...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7118205/ https://www.ncbi.nlm.nih.gov/pubmed/32292393 http://dx.doi.org/10.3389/fmicb.2020.00472 |
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author | Mohiuddin, Sayed Golam Hoang, Thuy Saba, Adesola Karki, Prashant Orman, Mehmet A. |
author_facet | Mohiuddin, Sayed Golam Hoang, Thuy Saba, Adesola Karki, Prashant Orman, Mehmet A. |
author_sort | Mohiuddin, Sayed Golam |
collection | PubMed |
description | Bacterial persisters are rare phenotypic variants that are temporarily tolerant to high concentrations of antibiotics. We have previously discovered that stationary-phase-cell subpopulations exhibiting high redox activities were less capable of producing proteins and resuming growth upon their dilution into fresh media. The redox activities of these cells were maintained by endogenous protein and RNA degradation, resulting in self-inflicted damage that transiently repressed the cellular functions targeted by antibiotics. Here, we showed that pretreatment of stationary-phase cells with an ATP synthase inhibitor, chlorpromazine hydrochloride (CPZ), significantly reduced stationary-phase-redox activities and protein degradation, and yielded cells that were more susceptible to cell death when exposed to antibiotics in fresh media. Leveraging this knowledge, we developed an assay integrating a degradable fluorescent protein system and a small library, containing FDA-approved drugs and antibiotics, to detect medically relevant drugs that potentially target persister metabolism. We identified a subset of chemical inhibitors, including polymyxin B, poly-L-lysine and phenothiazine anti-psychotic drugs, that were able to reduce the persistence phenotype in Escherichia coli. These chemical inhibitors also reduced Pseudomonas aeruginosa persistence, potentially verifying the existence of similar mechanisms in a medically relevant organism. |
format | Online Article Text |
id | pubmed-7118205 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-71182052020-04-14 Identifying Metabolic Inhibitors to Reduce Bacterial Persistence Mohiuddin, Sayed Golam Hoang, Thuy Saba, Adesola Karki, Prashant Orman, Mehmet A. Front Microbiol Microbiology Bacterial persisters are rare phenotypic variants that are temporarily tolerant to high concentrations of antibiotics. We have previously discovered that stationary-phase-cell subpopulations exhibiting high redox activities were less capable of producing proteins and resuming growth upon their dilution into fresh media. The redox activities of these cells were maintained by endogenous protein and RNA degradation, resulting in self-inflicted damage that transiently repressed the cellular functions targeted by antibiotics. Here, we showed that pretreatment of stationary-phase cells with an ATP synthase inhibitor, chlorpromazine hydrochloride (CPZ), significantly reduced stationary-phase-redox activities and protein degradation, and yielded cells that were more susceptible to cell death when exposed to antibiotics in fresh media. Leveraging this knowledge, we developed an assay integrating a degradable fluorescent protein system and a small library, containing FDA-approved drugs and antibiotics, to detect medically relevant drugs that potentially target persister metabolism. We identified a subset of chemical inhibitors, including polymyxin B, poly-L-lysine and phenothiazine anti-psychotic drugs, that were able to reduce the persistence phenotype in Escherichia coli. These chemical inhibitors also reduced Pseudomonas aeruginosa persistence, potentially verifying the existence of similar mechanisms in a medically relevant organism. Frontiers Media S.A. 2020-03-27 /pmc/articles/PMC7118205/ /pubmed/32292393 http://dx.doi.org/10.3389/fmicb.2020.00472 Text en Copyright © 2020 Mohiuddin, Hoang, Saba, Karki and Orman. 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 Mohiuddin, Sayed Golam Hoang, Thuy Saba, Adesola Karki, Prashant Orman, Mehmet A. Identifying Metabolic Inhibitors to Reduce Bacterial Persistence |
title | Identifying Metabolic Inhibitors to Reduce Bacterial Persistence |
title_full | Identifying Metabolic Inhibitors to Reduce Bacterial Persistence |
title_fullStr | Identifying Metabolic Inhibitors to Reduce Bacterial Persistence |
title_full_unstemmed | Identifying Metabolic Inhibitors to Reduce Bacterial Persistence |
title_short | Identifying Metabolic Inhibitors to Reduce Bacterial Persistence |
title_sort | identifying metabolic inhibitors to reduce bacterial persistence |
topic | Microbiology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7118205/ https://www.ncbi.nlm.nih.gov/pubmed/32292393 http://dx.doi.org/10.3389/fmicb.2020.00472 |
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