dc.description.abstract |
The renewed global focus on malaria elimination and eradication through successful
reduction of Plasmodium transmissions by infected mosquitoes warrants the discovery
of effective anti-infectives targeting the transmissible parasite stages and their vectors.
Owing to the toxicity of primaquine, the only approved drug that is effective against the
stage V gametocytes, safer therapeutics are urgently needed to combat transmissions.
Recognition of the important role of plants in antimalarial drug discovery was first
through the isolation of quinine and artemisinin. However, few plant-derived agents
inhibit gametocytes development or sexual gametocytogenesis pathway to facilitate
transmission-blocking of malaria parasites, underscoring their unmet demand. In
addition, their underlying molecular mechanisms of action remain uncharacterized. This
necessitates discovery of new plant-derived malaria transmission-blocking agents
targeting the Plasmodium gametocytes and mosquito larvae. In the quest to expand the
malaria transmission-blocking chemical space and elucidate molecular targets, this study
evaluated extracts from 13 selected plants. The goal was to mine for potent malaria
control agents with novel molecular mechanisms of action. In addition, the impact of
most bioactive compound on mosquito vector fitness, and characterization of larvicidal
effects of Zanthoxylum chalybeum root constituents on mosquito larvae growth were
assessed. From the 13 plant extracts tested against Plasmodium falciparum multidrug resistant asexual parasites (PfW2 strain), two active antimalarial extracts from Prosopis
juliflora (IC50 1.02 µg/mL) and Cissampelos pariera (IC50 2.09 µg/mL) also exhibited
potent Plasmodium late-stage IV/V gametocytes from NF54 and human clinical isolates
within the submicromolar IC50 window. Based on LC-ESI-MS/MS analyses, the
observed antimalarial activity was found to be exerted by a known 2,3-dihydro-1H indolizidinium, juliprosopine from P. juliflora (IC50 0.604 µg/mL for D6 Plasmodium
isolate), and previously isolated bisbenzylisoquinoline (BBIQ), isoliensinine from C.
pariera (IC50 1.329 µg/mL for D6), respectively. The two antimalarial compounds
inhibited P. falciparum Dd2 trophozoites-to-schizont transformation of the 48-h
intraerythrocytic cycle suggesting impairment of cell cycle regulatory elements. Further
prioritized activity-profiling of juliprosopine showed potent blockade of Plasmodium
gametocytogenesis of NF54 strain by day 7 post-induction, without exerting deleterious
effects on female Anopheles mosquito survival and egg hatchability. Insights into the
possible molecular targets predicted similar parasite biological pathways predominantly
clustering into: protein modifications, cell cycle and chromatin remodeling, fatty acid
biosynthesis, and host cell protein export, described during late trophozoites and late stage IV/V gametocytes. Evaluation of Zanthoxylum chalybeum Engl (ZCE)(Rutaceae)
root constituents against mosquito larvae demonstrated dose-dependent biphasic effects
on larval treatment; (i) transient exposure to ZCE and its bioactive fraction (ZCFr.5)
inhibited acetylcholinesterase (AChE) activity thus inducing larval lethality and (ii)
growth retardation at sublethal doses. The half-maximal lethal concentrations (LC50) for
the mosquito larvae ranged between 1.58 – 12.26 ppm, exerted by 2-tridecanone,
palmitic acid (hexadecanoic acid), linoleic acid ((Z,Z)-9,12-octadecadienoic acid),
sesamin, β-caryophyllene, among other compounds identified in bioactive ZCFr.5
fraction. The observed larval growth retardation induced by ZCE root constituents were
exerted through intracellular transcriptional modulation of ecdysteroidogenic CYP450
genes. Collectively, the key findings of this study necessitate further explorative
optimizations of the identified molecules for the development of potential malaria
control interventions and functional mechanism validations |
en_US |
dc.description.sponsorship |
Dr. Joel L. Bargul, PhD
JKUAT, Kenya
Dr. James M. Mutunga, PhD
MKU, Kenya
Prof. Meshack A. Obonyo, PhD
Egerton University, Kenya
Dr. Ramadhan S. Mwakubambanya, PhD
Egerton University, Kenya |
en_US |