Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: Mohiuddin, Sayed Golam, Hoang, Thuy, Saba, Adesola, Karki, Prashant, Orman, Mehmet A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2020
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
_version_ 1783514512900489216
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
work_keys_str_mv AT mohiuddinsayedgolam identifyingmetabolicinhibitorstoreducebacterialpersistence
AT hoangthuy identifyingmetabolicinhibitorstoreducebacterialpersistence
AT sabaadesola identifyingmetabolicinhibitorstoreducebacterialpersistence
AT karkiprashant identifyingmetabolicinhibitorstoreducebacterialpersistence
AT ormanmehmeta identifyingmetabolicinhibitorstoreducebacterialpersistence