6 research outputs found
A novel derivative of thioridazine shows low toxicity and efficient activity against gram‐positive pathogens
Thioridazine hydrochloride (HCl) has been suggested as a promising antimicrobial helper compound for the treatment of infections with antimicrobial-resistant bacteria. Unfortunately, the therapeutic concentration of thioridazine HCl is generally higher than what can be tolerated clinically, in part due to its toxic side effects on the central nervous system. Therefore, we aimed to synthesize a less toxic thioridazine derivative that would still retain its properties as a helper compound. This resulted in a compound designated 1-methyl-2-(2-(2-(methylthio)-10H-phenothiazin-10-yl)ethyl)-1-pentylpiperidin-1-ium bromide (abbreviated T5), which exhibited low blood–brain barrier permeability. The lowest minimal inhibitory concentration (MIC) against Staphylococcus aureus exposed to the novel compound was reduced 32-fold compared to thioridazine HCl (from 32 µg/mL to 1 µg/mL). The MIC values for T5 against five Gram-positive pathogens ranged from 1 µg/mL to 8 µg/mL. In contrast to thioridazine HCl, T5 does not act synergistically with oxacillin. In silico predictive structure analysis of T5 suggests that an acceptably low toxicity and lack of induced cytotoxicity was demonstrated by a lactate dehydrogenase assay. Conclusively, T5 is suggested as a novel antimicrobial agent against Gram-positive bacteria. However, future pharmacokinetic and pharmacodynamic studies are needed to clarify the clinical potential of this novel discovery
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 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
Pyrrolidone-modified PAMAM dendrimers enhance anti-inflammatory potential of indomethacin in vitro
A Novel Promazine Derivative Shows High <i>in vitro </i>and <i>in vivo </i>Antimicrobial Activity Against <i>Staphylococcus aureus</i>
Complexes of Indomethacin with 4‑Carbomethoxy-pyrrolidone PAMAM Dendrimers Show Improved Anti-inflammatory Properties and Temperature-Dependent Binding and Release Profile
COX-2
inhibitors such as nonsteroidal anti-inflammatory drugs (NSAIDs)
are the most common treatment for chronic inflammatory diseases like
arthritis and atherosclerosis. However, they are associated with severe
side effects such as cardiovascular events or stomach bleeding, due
to coinhibition of other enzymes (COX1) and off-target accumulation.
PAMAM dendrimers can solubilize lipophilic drugs and increase their
circulation time; furthermore, PAMAM dendrimers seem to have some
accumulation in inflammatory sides. Three different generations of
4-carbomethoxypyrrolidone (Pyr) surface-modified PAMAM dendrimers
were complexed with the NSAID drug indomethacin, and their in-solution
thermodynamic profiles were studied by means of NMR experiments. The
binding stoichiometry was found dependent on solvent system and dendrimer
generation. Larger dendrimers (G3-Pyr) were found to bind indomethacin
through entropy driven binding mode, while G1-Pyr and G2-Pyr expressed
an enthalpy driven complex formation, which means that the binding
constants have a generational temperature dependency. G1/2-Pyr showed
reduced binding with increasing temperature, which could be important
for drug release at inflammatory sites, which have, in general, elevated
temperatures. In vitro studies elucidated that the indomethacin drug
remained its activity when delivered as a dendrimer–indomethacin
complex. A slight reduction in toxicity profile was noticed for G2/G3-Pyr-indomethacin
dendrimers. Both free indomethacin and dendrimer–indomethacin
complex inhibited a variety of pro-inflammatory cytokines in LPS treated
cells. However, only the indo–dendrimer complexes showed a
significant reduction of IL-1β in LPS-treated THP-1 cells, which
was not present in the control with free indomethacin
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 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