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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
medicine
Novel non-neuroleptic phenothiazines inhibit mycobacterium tuberculosis replication
Journal of Antimicrobial Chemotherapy, Volume 69, No. 6, Year 2014
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Description
Objectives: Phenothiazines are a commercially available class of psychotropic drugs known to show antituberculosis activity. At clinically relevant bactericidal doses, however, the psychotropic drugs produce undesirable side effects in addition to their neuroleptic properties. This study aimed to evaluate rationally designed novel phenothiazines as antimycobacterial drug candidates. Methods: Remodelling of psychotropic drugs by substitution of characteristic N-alkylamine side chains, important for CNS activity, with N-alkylsulphonates gave novel drug candidates, which were then tested for post-synaptic receptor binding affinity in a radioligand displacement assay. The bactericidal activities were screened using green fluorescent protein (GFP) microplate assays, and the efficacy of intracellular bacillus killing was evaluated by cfu enumeration. Results: Of the four selected phenothiazine derivatives (PTZ3, PTZ4, PTZ31 and PTZ32) tested, PTZ31 displayed marginal serotonergic activity. The remaining three derivatives did not exhibit dopamine or serotonin receptor binding activity. In vitro results showed significant growth inhibition of virulent Mycobacterium tuberculosis with MICs of 12.5-25 mg/L. None of the phenothiazine derivatives displayed cytotoxicity in infected primary bone marrow-derived macrophages. Moreover, the phenothiazines showed significant antimycobacterial activity of between 40% and 60% against intracellular (ex vivo) M. tuberculosis. Conclusions:We demonstrate that structural modification of the phenothiazine core is possible in a manner that does not affect the ability of the phenothiazine derivatives to inhibit M. tuberculosis, but that abolishes undesirable dopamine and serotonin receptor binding. © The Author 2014. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved.
Authors & Co-Authors
Salie, Sumayah
South Africa, Cape Town
University of Cape Town
Hsu, Nai Jen
South Africa, Cape Town
University of Cape Town
Semenya, Dorothy M.
South Africa, Cape Town
Faculty of Health Sciences
Jardine, Anwar M.
South Africa, Cape Town
Faculty of Health Sciences
Jacobs, Muazzam
South Africa, Cape Town
University of Cape Town
South Africa, Johannesburg
National Health Laboratory Service
Statistics
Citations: 14
Authors: 5
Affiliations: 3
Identifiers
Doi:
10.1093/jac/dku036
ISSN:
03057453
e-ISSN:
14602091
Research Areas
Cancer