Kim, Caroline Ewha; (2008) Stimulation of macrophage uptake and killing of mycobacteria by compounds derived from the roots of Pelargonium spp. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Background: The development of new treatments for tuberculosis is a public health priority. We have shown that a South African native remedy for respiratory ailments, based on extracts of Pelargonium reniforme and P. sidoides, contain fatty acids with antimycobacterial activity. In order to further assess their potential as a supplement to conventional therapy, we examined root extracts of these plants for the capacity to stimulate the uptake and intracellular killing of mycobacteria by macrophages. Methods: Murine peritoneal macrophages were obtained by lavage and incubated with Mycobacterium fortuitum. Extract-mediated stimulation of bacterial uptake was determined by enumeration of stained intracellular bacteria; the effect of extracts on intracellular killing was evaluated by spread plate counting of bacteria within macrophages. Bioactive extracts, obtained by sequential extraction with solvents of increasing polarity, were subjected to bioassay-guided fractionation using size exclusion and ion exchange chromatography. HPLC, NMR and mass spectroscopy were used to identify compounds of interest. Active compounds were examined for their capacity to stimulate macrophage uptake of M. tuberculosis. Results: Root powders were sequentially extracted with hexane, ethyl acetate, ethanol, 50% ethanol/water and water; aqueous fractions had a greater capacity to stimulate uptake and killing of M. fortuitum compared to other fractions. P. reniforme extracts possessed significantly greater stimulating activity than P. sidoides extracts. Fractions obtained by bioassay-guided fractionation of P. reniforme aqueous extracts contained a small number of chemically distinct structures, the most prominent being gallic acid, methyl gallate, myricetin and quercetin 3-D-glucoside. Highly pure preparations of these compounds (2-25 μg/ml) stimulated macrophage killing of M fortuitum and M tuberculosis. Conclusion: Representatives of the plant genus Pelargonium elaborate metabolites that increase the capacity of mice peritoneal macrophages to internalize and kill mycobacteria, including M. tuberculosis.

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