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Warman, Ashley, Rito, Teresa S, Fisher, Nicholas, Moss, Darren M., Berry, Neil G, O'Neill, Paul M, Ward, Stephen 
ORCID: https://orcid.org/0000-0003-2331-3192 and Biagini, Giancarlo ORCID: https://orcid.org/0000-0001-6356-6595
(2013)
'Antitubercular pharmacodynamics of phenothiazines'. Journal of Antimicrobial Chemotherapy, Vol 68, Issue 4, pp. 869-880.
Abstract
OBJECTIVES: Phenothiazines 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. METHODS: Recombinant Mtb Ndh was generated and its functionality confirmed by steady-state kinetics. Pharmacodynamic profiling of the phenothiazines, including antitubercular efficacy in aerobic and O(2)-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 bc(1). RESULTS: Steady-state kinetic analyses revealed a substrate preference for coenzyme Q(2) 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. CONCLUSIONS: Data 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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | tuberculosis, thioridazine, Ndh, latency, toxicity |
| Subjects: | QV Pharmacology > QV 38 Drug action. QV Pharmacology > Drug Standardization. Pharmacognosy. Medicinal Plants > QV 744 Pharmaceutical chemistry QV Pharmacology > Drug Standardization. Pharmacognosy. Medicinal Plants > QV 771 Standardization and evaluation of drugs WF Respiratory System > Tuberculosis > WF 200 Tuberculosis (General) |
| Faculty: Department: | Biological Sciences > Department of Tropical Disease Biology |
| Digital Object Identifer (DOI): | https://doi.org/10.1093/jac/dks483 |
| Depositing User: | Mary Creegan |
| Date Deposited: | 22 Apr 2013 11:31 |
| Last Modified: | 06 Feb 2018 13:06 |
| URI: | https://archive.lstmed.ac.uk/id/eprint/3316 |
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