ArticleThe Journal of antimicrobial chemotherapy2013
Antitubercular pharmacodynamics of phenothiazines.
Article in The Journal of antimicrobial chemotherapy, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Who cites it
26 citing papers in PubMed, 59 citations in OpenAlex.
- Combination strategies targeting multiple ETC subunits as a rational approach for drug-resistant TB therapy.Archives of microbiology · 2026Review
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- Discovery of Biofilm-Inhibiting Compounds to Enhance Antibiotic Effectiveness AgainstPharmaceuticals (Basel, Switzerland) · 2025Article
- Regio- and diastereoselective synthesis of cyclobutylated phenothiazinesChemical science · 2025Article
- Polyphosphate kinase-1 regulates bacterial and host metabolic pathways involved in pathogenesis ofProceedings of the National Academy of Sciences of the United States of America · 2024Article
- Identification of 2-Aryl-Quinolone Inhibitors of CytochromeACS infectious diseases · 2023Article
- Design, Synthesis and Antimicrobial Properties of New Tetracyclic Quinobenzothiazine Derivatives.International journal of molecular sciences · 2022Article
- Antioxidant Properties of New Phenothiazine Derivatives.Antioxidants (Basel, Switzerland) · 2022Article
- Towards Property Profiling: SYNTHESIS and SAR Probing of New Tetracyclic Diazaphenothiazine Analogues.International journal of molecular sciences · 2021Article
- Copper-Loaded Layered Bismuth Subcarbonate-Efficient Multifunctional Heterogeneous Catalyst for Concerted C-S/C-N Heterocyclization.ACS applied materials & interfaces · 2021Article
- Dual inhibition of the terminal oxidases eradicates antibiotic-tolerant Mycobacterium tuberculosis.EMBO molecular medicine · 2021Article
- Siderophore-Antibiotic Conjugate Design: New Drugs for Bad Bugs?Molecules (Basel, Switzerland) · 2019Review
- Inhibitors of energy metabolism interfere with antibiotic-induced death in mycobacteria.The Journal of biological chemistry · 2019Article
- The Application of CA and PCA to the Evaluation of Lipophilicity and Physicochemical Properties of Tetracyclic Diazaphenothiazine Derivatives.Journal of analytical methods in chemistry · 2019Article
- Small Molecules Targeting Mycobacterium tuberculosis Type II NADH Dehydrogenase Exhibit Antimycobacterial Activity.Angewandte Chemie (International ed. in English) · 2018Article
- Challenging the Drug-Likeness Dogma for New Drug Discovery in Tuberculosis.Frontiers in microbiology · 2018Review
- Oxidative Phosphorylation as a Target Space for Tuberculosis: Success, Caution, and Future Directions.Microbiology spectrum · 2017Review
- Pharmacokinetic-Pharmacodynamic modelling of intracellular Mycobacterium tuberculosis growth and kill rates is predictive of clinical treatment duration.Scientific reports · 2017Article
- The mechanism of catalysis by type-II NADH:quinone oxidoreductases.Scientific reports · 2017Article
- Thioridazine inhibits gene expression control of the cell wall signaling pathway (CWI) in the human pathogenic fungus Paracoccidioides brasiliensis.Molecular genetics and genomics : MGG · 2016Article
Corrections and comments
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Authors and funding
8 authors at 2 institutions in 1 country.
Funding
Abstract
objectivesPhenothiazines have been shown to exhibit in vitro and in vivo activity against Mycobacterium tuberculosis (Mtb) and multidrug-resistant Mtb. They are predicted to target the genetically validated respiratory chain component type II NADH:quinone oxidoreductase (Ndh). Using a set of compounds containing the phenothiazine pharmacophore, we have (i) investigated whether chemical validation data support the molecular target and (ii) evaluated pharmacophore tractability for further drug development.
methodsRecombinant Mtb Ndh was generated and its functionality confirmed by steady-state kinetics. Pharmacodynamic profiling of the phenothiazines, including antitubercular efficacy in aerobic and O2-limited conditions, time-kill assays and isobole analyses against first-line antituberculars, was performed. Potential mitochondrial toxicity was assessed in a modified HepG2 cell-line assay and against bovine cytochrome bc1.
resultsSteady-state kinetic analyses revealed a substrate preference for coenzyme Q2 and an inability to utilize NADPH. A positive correlation between recombinant Ndh inhibition and kill of aerobically cultured Mtb was observed, whilst enhanced potency was demonstrated in a hypoxic model. Time-kill studies revealed the phenothiazines to be bactericidal whilst isobolograms exposed antagonism with isoniazid, indicative of intracellular NADH/NAD(+) couple perturbation. At therapeutic levels, phenothiazine-mediated toxicity was appreciable; however, specific mitochondrial targeting was excluded.
conclusionsData generated support the hypothesis that Ndh is the molecular target of phenothiazines. The favourable pharmacodynamic properties of the phenothiazines are consistent with a target product profile that includes activity against dormant/persistent bacilli, rapid bactericidal activity and activity against drug-resistant Mtb by a previously unexploited mode of action. These properties warrant further medicinal chemistry to improve potency and safety.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.