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Insight Into the Anti-staphylococcal Activity of JBC 1847 at Sub-Inhibitory Concentration

Multidrug-resistant pathogens constitute a serious global issue and, therefore, novel antimicrobials with new modes of action are urgently needed. Here, we investigated the effect of a phenothiazine derivative (JBC 1847) with high antimicrobial activity on Staphylococcus aureus, using a wide range o...

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Autores principales: Ronco, Troels, Kappel, Line H., Aragao, Maria F., Biagi, Niccolo, Svenningsen, Søren, Christensen, Jørn B., Permin, Anders, Saaby, Lasse, Holmstrøm, Kim, Klitgaard, Janne K., Sabat, Artur J., Akkerboom, Viktoria, Monaco, Monica, Tinelli, Marco, Friedrich, Alexander W., Jana, Bimal, Olsen, Rikke H.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8766816/
https://www.ncbi.nlm.nih.gov/pubmed/35069485
http://dx.doi.org/10.3389/fmicb.2021.786173
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author Ronco, Troels
Kappel, Line H.
Aragao, Maria F.
Biagi, Niccolo
Svenningsen, Søren
Christensen, Jørn B.
Permin, Anders
Saaby, Lasse
Holmstrøm, Kim
Klitgaard, Janne K.
Sabat, Artur J.
Akkerboom, Viktoria
Monaco, Monica
Tinelli, Marco
Friedrich, Alexander W.
Jana, Bimal
Olsen, Rikke H.
author_facet Ronco, Troels
Kappel, Line H.
Aragao, Maria F.
Biagi, Niccolo
Svenningsen, Søren
Christensen, Jørn B.
Permin, Anders
Saaby, Lasse
Holmstrøm, Kim
Klitgaard, Janne K.
Sabat, Artur J.
Akkerboom, Viktoria
Monaco, Monica
Tinelli, Marco
Friedrich, Alexander W.
Jana, Bimal
Olsen, Rikke H.
author_sort Ronco, Troels
collection PubMed
description Multidrug-resistant pathogens constitute a serious global issue and, therefore, novel antimicrobials with new modes of action are urgently needed. Here, we investigated the effect of a phenothiazine derivative (JBC 1847) with high antimicrobial activity on Staphylococcus aureus, using a wide range of in vitro assays, flow cytometry, and RNA transcriptomics. The flow cytometry results showed that JBC 1847 rapidly caused depolarization of the cell membrane, while the macromolecule synthesis inhibition assay showed that the synthesis rates of DNA, RNA, cell wall, and proteins, respectively, were strongly decreased. Transcriptome analysis of S. aureus exposed to sub-inhibitory concentrations of JBC 1847 identified a total of 78 downregulated genes, whereas not a single gene was found to be significantly upregulated. Most importantly, there was downregulation of genes involved in adenosintrifosfat (ATP)-dependent pathways, including histidine biosynthesis, which is likely to correlate with the observed lower level of intracellular ATP in JBC 1847–treated cells. Furthermore, we showed that JBC 1847 is bactericidal against both exponentially growing cells and cells in a stationary growth phase. In conclusion, our results showed that the antimicrobial properties of JBC 1847 were primarily caused by depolarization of the cell membrane resulting in dissipation of the proton motive force (PMF), whereby many essential bacterial processes are affected. JBC 1847 resulted in lowered intracellular levels of ATP followed by decreased macromolecule synthesis rate and downregulation of genes essential for the amino acid metabolism in S. aureus. Bacterial compensatory mechanisms for this proposed multi-target activity of JBC 1847 seem to be limited based on the observed very low frequency of resistance toward the compound.
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spelling pubmed-87668162022-01-20 Insight Into the Anti-staphylococcal Activity of JBC 1847 at Sub-Inhibitory Concentration Ronco, Troels Kappel, Line H. Aragao, Maria F. Biagi, Niccolo Svenningsen, Søren Christensen, Jørn B. Permin, Anders Saaby, Lasse Holmstrøm, Kim Klitgaard, Janne K. Sabat, Artur J. Akkerboom, Viktoria Monaco, Monica Tinelli, Marco Friedrich, Alexander W. Jana, Bimal Olsen, Rikke H. Front Microbiol Microbiology Multidrug-resistant pathogens constitute a serious global issue and, therefore, novel antimicrobials with new modes of action are urgently needed. Here, we investigated the effect of a phenothiazine derivative (JBC 1847) with high antimicrobial activity on Staphylococcus aureus, using a wide range of in vitro assays, flow cytometry, and RNA transcriptomics. The flow cytometry results showed that JBC 1847 rapidly caused depolarization of the cell membrane, while the macromolecule synthesis inhibition assay showed that the synthesis rates of DNA, RNA, cell wall, and proteins, respectively, were strongly decreased. Transcriptome analysis of S. aureus exposed to sub-inhibitory concentrations of JBC 1847 identified a total of 78 downregulated genes, whereas not a single gene was found to be significantly upregulated. Most importantly, there was downregulation of genes involved in adenosintrifosfat (ATP)-dependent pathways, including histidine biosynthesis, which is likely to correlate with the observed lower level of intracellular ATP in JBC 1847–treated cells. Furthermore, we showed that JBC 1847 is bactericidal against both exponentially growing cells and cells in a stationary growth phase. In conclusion, our results showed that the antimicrobial properties of JBC 1847 were primarily caused by depolarization of the cell membrane resulting in dissipation of the proton motive force (PMF), whereby many essential bacterial processes are affected. JBC 1847 resulted in lowered intracellular levels of ATP followed by decreased macromolecule synthesis rate and downregulation of genes essential for the amino acid metabolism in S. aureus. Bacterial compensatory mechanisms for this proposed multi-target activity of JBC 1847 seem to be limited based on the observed very low frequency of resistance toward the compound. Frontiers Media S.A. 2022-01-05 /pmc/articles/PMC8766816/ /pubmed/35069485 http://dx.doi.org/10.3389/fmicb.2021.786173 Text en Copyright © 2022 Ronco, Kappel, Aragao, Biagi, Svenningsen, Christensen, Permin, Saaby, Holmstrøm, Klitgaard, Sabat, Akkerboom, Monaco, Tinelli, Friedrich, Jana and Olsen. https://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
Ronco, Troels
Kappel, Line H.
Aragao, Maria F.
Biagi, Niccolo
Svenningsen, Søren
Christensen, Jørn B.
Permin, Anders
Saaby, Lasse
Holmstrøm, Kim
Klitgaard, Janne K.
Sabat, Artur J.
Akkerboom, Viktoria
Monaco, Monica
Tinelli, Marco
Friedrich, Alexander W.
Jana, Bimal
Olsen, Rikke H.
Insight Into the Anti-staphylococcal Activity of JBC 1847 at Sub-Inhibitory Concentration
title Insight Into the Anti-staphylococcal Activity of JBC 1847 at Sub-Inhibitory Concentration
title_full Insight Into the Anti-staphylococcal Activity of JBC 1847 at Sub-Inhibitory Concentration
title_fullStr Insight Into the Anti-staphylococcal Activity of JBC 1847 at Sub-Inhibitory Concentration
title_full_unstemmed Insight Into the Anti-staphylococcal Activity of JBC 1847 at Sub-Inhibitory Concentration
title_short Insight Into the Anti-staphylococcal Activity of JBC 1847 at Sub-Inhibitory Concentration
title_sort insight into the anti-staphylococcal activity of jbc 1847 at sub-inhibitory concentration
topic Microbiology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8766816/
https://www.ncbi.nlm.nih.gov/pubmed/35069485
http://dx.doi.org/10.3389/fmicb.2021.786173
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