Insight Into the Anti-staphylococcal Activity of JBC 1847 at Sub-Inhibitory Concentration
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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.
In: Frontiers in Microbiology, Vol. 12, 786173, 2022.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Insight Into the Anti-staphylococcal Activity of JBC 1847 at Sub-Inhibitory Concentration
AU - Ronco, Troels
AU - Kappel, Line H.
AU - Aragao, Maria F.
AU - Biagi, Niccolo
AU - Svenningsen, Søren
AU - Christensen, Jørn B.
AU - Permin, Anders
AU - Saaby, Lasse
AU - Holmstrøm, Kim
AU - Klitgaard, Janne K.
AU - Sabat, Artur J.
AU - Akkerboom, Viktoria
AU - Monaco, Monica
AU - Tinelli, Marco
AU - Friedrich, Alexander W.
AU - Jana, Bimal
AU - Olsen, Rikke H.
N1 - Publisher Copyright: Copyright © 2022 Ronco, Kappel, Aragao, Biagi, Svenningsen, Christensen, Permin, Saaby, Holmstrøm, Klitgaard, Sabat, Akkerboom, Monaco, Tinelli, Friedrich, Jana and Olsen.
PY - 2022
Y1 - 2022
N2 - 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.
AB - 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.
KW - antimicrobial resistance
KW - Gram-positive bacteria
KW - mode of action
KW - phenothiazine derivative
KW - RNA transcriptomics
U2 - 10.3389/fmicb.2021.786173
DO - 10.3389/fmicb.2021.786173
M3 - Journal article
C2 - 35069485
AN - SCOPUS:85123106742
VL - 12
JO - Frontiers in Microbiology
JF - Frontiers in Microbiology
SN - 1664-302X
M1 - 786173
ER -
ID: 291222891