The repurposing of anti-malarial as anti-cryptococcal drugs
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Date
2020-05
Authors
Madu, Lynda Uju
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Publisher
University of the Free State
Abstract
The safety and effectiveness of anti-fungal medicines are paramount to controlling the growth of pathogenic fungi. Following the isolation of Cryptococcus neoformans and documenting evidence that it as an aetiological agent of an often-deadly inflammatory condition of the brain, more so in people with immunosuppressive conditions, the quest to find alternative (including complementary) medicines has continued until now. The major shortcoming that is associated with the currently used anti-fungal medicines, i.e. fluconazole and amphotericin B, in South Africa, is clinical failure. This, in turn, has led to increased mortality. With the thesis, it was aimed to understand the response of cryptococcal cells towards antimalarial drugs, CQ and PQ. In chapter 2 it was illustrated that cryptococcal cells are sensitive to light inactivation following exposure to a germicidal UV light (UVC) in the presence of CQ and PQ (both used as photosensitisers) as well as ambient air. The yielded photolytic products targeted the membranes that, in turn, led to cell death. Moreover, the treatment of internalised cryptococcal cells led to their increased sensitivity towards macrophage phagocytosis killing. Chapter 3 highlighted the importance of PQ in controlling the growth of cryptococcal cells. The data revealed that PQ targeted cryptococcal mitochondria, an important organelle of this organisms. Given the dependence of the organism on this organelle to produce energy to sustain it, its impaired resulted in cells being vulnerable and subsequently dying. The drug also enhanced the macrophages’ phagocytosis efficiency to kill internalised cryptococcal cells. Chapter 4 considered using a lipophilic-based medium to deliver CQ, in an attempt to control of disseminated infection. The prepared TPGS-CQ micelle was then used in an in vitro blood-brain barrier (BBB) model, set up using a transwell plate, to control cryptococcal cells. While the micelle was not efficient in delivering the CQ, the minimal amounts that were delivered were sufficient to significantly control the growth of cryptococcal cells. Based on these findings, it is clear that there is merit in considering CQ and PQ in the management of cryptococcal cells. The drugs could be used to complement the currently used antifungal drugs in combined therapy to establish synergism. The latter would imply that minimal concentrations would be required – thus, minimise chances to manifesting side effects. Moreover, in vivo studies ought to be conducted. These would be important in the establishment of their safety profiles and effectiveness a complex, eukaryotic animal like rats. To date, there are reports that highlight limitations concerning the clinical use of these drugs. These include patients underlying heart conditions as well as those with glucose 6-phosphate dehydrogenase deficiency, an enzyme that helps protect red blood cells from damage. To this end, rats with such defects can also be included in such studies for referencing purposes.
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Keywords
Thesis (Ph.D. (Microbial, Biochemical and Food Biotechnology))--University of the Free State, 2020, Blood-brain barrier, Chloroquine, Cryptococcus, CQ-TPGS, Drug-repurposing, hCMEC/D3, Macrophages, Mitochondria, Photodynamic therapy, Photosensitisers, Primaquine.