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Communications Biology Mar 2022Bacterial persister cells are temporarily tolerant to bactericidal antibiotics but are not necessarily dormant and may exhibit physiological activities leading to cell...
Bacterial persister cells are temporarily tolerant to bactericidal antibiotics but are not necessarily dormant and may exhibit physiological activities leading to cell damage. Based on the link between fluoroquinolone-mediated SOS responses and persister cell recovery, we screened chemicals that target fluoroquinolone persisters. Metabolic inhibitors (e.g., phenothiazines) combined with ofloxacin (OFX) perturbed persister levels in metabolically active cell populations. When metabolically stimulated, intrinsically tolerant stationary phase cells also became OFX-sensitive in the presence of phenothiazines. The effects of phenothiazines on cell metabolism and physiology are highly pleiotropic: at sublethal concentrations, phenothiazines reduce cellular metabolic, transcriptional, and translational activities; impair cell repair and recovery mechanisms; transiently perturb membrane integrity; and disrupt proton motive force by dissipating the proton concentration gradient across the cell membrane. Screening a subset of mutant strains lacking membrane-bound proteins revealed the pleiotropic effects of phenothiazines potentially rely on their ability to inhibit a wide range of critical metabolic proteins. Altogether, our study further highlights the complex roles of metabolism in persister cell formation, survival and recovery, and suggests metabolic inhibitors such as phenothiazines can be selectively detrimental to persister cells.
Topics: Anti-Bacterial Agents; Escherichia coli; Fluoroquinolones; Gram-Negative Bacteria; Phenothiazines
PubMed: 35264714
DOI: 10.1038/s42003-022-03172-8 -
British Medical Journal Jul 1977
Topics: Antipsychotic Agents; Drug Resistance; Electroconvulsive Therapy; Humans; Phenothiazines; Schizophrenia
PubMed: 17450
DOI: 10.1136/bmj.2.6079.127-b -
Redox Biology Jun 2019Impaired mitochondrial function has been associated with the etiopathogenesis of Parkinson's disease (PD). Sustained inhibition of complex I produces mitochondrial...
Phenothiazine normalizes the NADH/NAD ratio, maintains mitochondrial integrity and protects the nigrostriatal dopamine system in a chronic rotenone model of Parkinson's disease.
Impaired mitochondrial function has been associated with the etiopathogenesis of Parkinson's disease (PD). Sustained inhibition of complex I produces mitochondrial dysfunction, which is related to oxidative injury and nigrostriatal dopamine (DA) neurodegeneration. This study aimed to identify disease-modifying treatments for PD. Unsubstituted phenothiazine (PTZ) is a small and uncharged aromatic imine that readily crosses the blood-brain barrier. PTZ lacks significant DA receptor-binding activity and, in the nanomolar range, exhibits protective effects via its potent free radical scavenging and anti-inflammatory activities. Given that DAergic neurons are highly vulnerable to oxidative damage and inflammation, we hypothesized that administration of PTZ might confer neuroprotection in different experimental models of PD. Our findings showed that PTZ rescues rotenone (ROT) toxicity in primary ventral midbrain neuronal cultures by preserving neuronal integrity and reducing protein thiol oxidation. Long-term treatment with PTZ improved animal weight, survival rate, and behavioral deficits in ROT-lesioned rats. PTZ protected DA content and fiber density in the striatum and DA neurons in the SN against the deleterious effects of ROT. Mitochondrial dysfunction, axonal impairment, oxidative insult, and inflammatory response were attenuated with PTZ therapy. Furthermore, we have provided a new insight into the molecular mechanism underlying the neuroprotective effects of PTZ.
Topics: Animals; Biomarkers; Cell Culture Techniques; Corpus Striatum; Dopamine; Dopaminergic Neurons; Dose-Response Relationship, Drug; Immunohistochemistry; Male; Mitochondria; Models, Biological; NAD; Neuroprotection; Neuroprotective Agents; Parkinson Disease; Phenothiazines; Rats; Rotenone; Substantia Nigra
PubMed: 30925294
DOI: 10.1016/j.redox.2019.101164 -
Journal of Medicinal Chemistry Feb 2019The phenothiazine system was identified as a favorable cap group for potent and selective histone deacetylase 6 (HDAC6) inhibitors. Here, we report the preparation and...
The phenothiazine system was identified as a favorable cap group for potent and selective histone deacetylase 6 (HDAC6) inhibitors. Here, we report the preparation and systematic variation of phenothiazines and their analogues containing a benzhydroxamic acid moiety as the zinc-binding group. We evaluated their ability to selectively inhibit HDAC6 by a recombinant HDAC enzyme assay, by determining the protein acetylation levels in cells by western blotting (tubulin vs histone acetylation), and by assessing their effects on various cancer cell lines. Structure-activity relationship studies revealed that incorporation of a nitrogen atom into the phenothiazine framework results in increased potency and selectivity for HDAC6 (more than 500-fold selectivity relative to the inhibition of HDAC1, HDAC4, and HDAC8), as rationalized by molecular modeling and docking studies. The binding mode was confirmed by co-crystallization of the potent azaphenothiazine inhibitor with catalytic domain 2 from Danio rerio HDAC6.
Topics: Acetylation; Animals; Catalytic Domain; Cells, Cultured; Crystallography, X-Ray; HL-60 Cells; Histone Deacetylase 6; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; In Vitro Techniques; Microsomes, Liver; Molecular Docking Simulation; Molecular Structure; Phenothiazines; Structure-Activity Relationship; Zebrafish
PubMed: 30645113
DOI: 10.1021/acs.jmedchem.8b01090 -
Biosensors Jan 2024A new fluorescent sensor for the detection of CN was developed based on the conjugation of phenothiazine fluorophore and benzofuran unit. By the nucleophilic attacking...
A new fluorescent sensor for the detection of CN was developed based on the conjugation of phenothiazine fluorophore and benzofuran unit. By the nucleophilic attacking of CN to the fluoroacetylamino group in the sensor, the additional reaction of CN and carbonyl group induced the ICT (intramolecular charge transfer) effect in the molecule and caused the fluorescence quenching sensor. The titration experiments show that the sensor has good sensitivity, selectivity and quick response for CN. In addition, the fluorescent detection of CN in the living cell and zebrafish experiments demonstrated the value of the sensor in tracing the CN in biological systems.
Topics: Animals; Cyanides; Zebrafish; Fluorescent Dyes; Phenothiazines
PubMed: 38248428
DOI: 10.3390/bios14010051 -
Transactions of the American... 1962
Topics: Antipsychotic Agents; Phenothiazines; Pigments, Biological; Uvea
PubMed: 13985756
DOI: No ID Found -
Postgraduate Medical Journal Apr 1968
Review
Topics: Amphetamine; Antidepressive Agents; Barbiturates; Chlorpromazine; Hallucinogens; Haloperidol; Hypnotics and Sedatives; Imipramine; Lithium; Lysergic Acid Diethylamide; Monoamine Oxidase Inhibitors; Phenothiazines; Tranquilizing Agents
PubMed: 4870139
DOI: 10.1136/pgmj.44.510.286 -
Biomolecules Sep 2016There is a need to identify novel scaffolds and targets to develop new antibiotics. Methylene blue is a phenothiazine derivative, and it has been shown to possess...
There is a need to identify novel scaffolds and targets to develop new antibiotics. Methylene blue is a phenothiazine derivative, and it has been shown to possess anti-malarial and anti-trypanosomal activities. Here, we show that different phenothiazine derivatives and pyronine G inhibited the activities of three structurally different bacterial RNase P RNAs (RPRs), including that from Mycobacterium tuberculosis, with Ki values in the lower μM range. Interestingly, three antipsychotic phenothiazines (chlorpromazine, thioridazine, and trifluoperazine), which are known to have antibacterial activities, also inhibited the activity of bacterial RPRs, albeit with higher Ki values than methylene blue. Phenothiazines also affected lead(II)-induced cleavage of bacterial RPR and inhibited yeast tRNA(Phe), indicating binding of these drugs to functionally important regions. Collectively, our findings provide the first experimental data showing that long, noncoding RNAs could be targeted by different phenothiazine derivatives.
Topics: Anti-Bacterial Agents; Antipsychotic Agents; Bacterial Proteins; Lead; Phenothiazines; RNA, Bacterial; RNA, Fungal; RNA, Transfer; Ribonuclease P
PubMed: 27618117
DOI: 10.3390/biom6030038 -
Scientific Reports Jun 2023Assessing the in vitro toxicity of compounds on cell cultures is an important step during the screening of candidate molecules for diverse applications. Among the...
Assessing the in vitro toxicity of compounds on cell cultures is an important step during the screening of candidate molecules for diverse applications. Among the strategies employed to determine cytotoxicity, MTT, neutral red, and resazurin are commonly used. Methylene blue (MB), a phenothiazinium salt, has several uses, such as dye, redox indicator, and even as treatment for human disease and health conditions, such as malaria and methemoglobinemia. However, MB has only been sparsely used as a cellular toxicity indicator. As a viability indicator, MB is mostly applied to fixed cultures at high concentrations, especially when compared to MTT or neutral red. Here we show that MB and its related compounds new methylene blue (NMB), toluidine blue O (TBO), and dimethylmethylene blue (DMMB) can be used as cytotoxicity indicators in live (non-fixed) cells treated for 72 h with DMSO and cisplatin. We compared dye uptake between phenothiazinium dyes and neutral red by analyzing supernatant and cell content via visible spectra scanning and microscopy. All dyes showed a similar ability to assess cell toxicity compared to either MTT or neutral red. Our method represents a cost-effective alternative to in vitro cytotoxicity assays using cisplatin or DMSO, indicating the potential of phenothiazinium dyes for the screening of candidate drugs and other applications.
Topics: Humans; Coloring Agents; Phenothiazines; Cisplatin; Neutral Red; Dimethyl Sulfoxide; Methylene Blue
PubMed: 37353536
DOI: 10.1038/s41598-023-36721-0 -
International Journal of Molecular... Jun 2017The molecular frame of the reported series of new polyheterocyclic compounds was intended to combine the potent phenothiazine and benzothiazole pharmacophoric units. The...
The molecular frame of the reported series of new polyheterocyclic compounds was intended to combine the potent phenothiazine and benzothiazole pharmacophoric units. The synthetic strategy applied was based on oxidative cyclization of -(phenothiazin-3-yl)-thioamides and it was validated by the preparation of new 2-alkyl- and 2-aryl-thiazolo[5,4-]phenothiazine derivatives. Optical properties of the series were experimentally emphasized by UV-Vis absorption/emission spectroscopy and structural features were theoretically modelled using density functional theory (DFT). In vitro activity as antileukemic agents of thiazolo[5,4-]phenothiazine and -(phenothiazine-3-yl)-thioamides were comparatively evaluated using cultivated HL-60 human promyelocytic and THP-1 human monocytic leukaemia cell lines. Some representatives proved selectivity against tumour cell lines, cytotoxicity, apoptosis induction, and cellular metabolism impairment capacity. 2-Naphthyl-thiazolo[5,4-]phenothiazine was identified as the most effective of the series by displaying against THP-1 cell lines a cytotoxicity close to cytarabine antineoplastic agent.
Topics: Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cell Proliferation; HL-60 Cells; Humans; Leukemia; Models, Molecular; Molecular Conformation; Molecular Structure; Phenothiazines; Spectrum Analysis; Structure-Activity Relationship
PubMed: 28672876
DOI: 10.3390/ijms18071365