Stage-dependent activity of curcumin-rosmarinic acid against Leishmania donovani: Synergy in amastigotes
4 affiliations
- 1West African Centre for Cell Biology of Infectious Pathogens, University of Ghana, Accra, Ghana
- 2Department of Biochemistry, Cell and Molecular Biology, University of Ghana, Accra, Ghana
- 3Institute of Medical Research and Medicinal Plants Studies (IMPM), Yaoundé, Cameroon
- 4Department of Life Sciences, Imperial College, London, United Kingdom
Abstract
Background: Leishmania donovani causes visceral leishmaniasis, a severe and fatal parasitic disease that affects the world’s most impoverished populations. Iron metabolism is fundamental in parasite survival and host immunity. In this study, we investigated the potential use of iron-chelating compounds to inhibit intracellular L. donovani through host regulation of iron metabolism and macrophage activation. Methods: Four phenolic compounds (curcumin, rosmarinic acid, apigenin, and hesperidin) were screened individually and in fixed-ratio combinations against L. donovani promastigotes and intracellular amastigotes cultured in RAW 264.7 murine macrophages. Drug interactions were assessed using the overall mean fractional inhibitory concentration index (x―ƩFICI) averaged across four fixed ratios. Mechanistic approaches involved measuring intracellular iron, reactive oxygen species (ROS) and nitrite production, macrophage cytokine profiles, and iron-regulatory gene expression. Results: The Curcumin-rosmarinic acid (Cur-Ros) combination exhibited stage-dependent activity: additive effects against promastigotes (x―ƩFICI = 0.93) but synergistic effects, though close to the threshold, against intracellular amastigotes (x―ƩFICI = 0.49), with selectivity indexes (SI) ≥10. Treatments enhanced pro-inflammatory macrophage activation characterized by increased secretion of Tumor Necrosis Factor-alpha (TNF-α) and Monocyte chemoattractant protein-1 (MCP-1). There were decreased interleukin-10 (IL-10) levels, enhanced ROS and nitrite production, and reduced intracellular iron availability. Gene expression analysis indicated upregulation of NRAMP1 (SLC11A1, a phagosomal divalent metal transporter) and downregulation of ferritin, consistent with altered iron homeostasis. Conclusions: In this study, curcumin-rosmarinic acid combinations inhibited growth of intracellular L. donovani amastigotes synergistically, correlating with macrophage activation and altered iron homeostasis. These findings identify curcumin-rosmarinic acid as a synergistic combination warranting further investigation with appropriate formulation and in vivo validation. Author summary: Leishmaniasis remains a worldwide health threat requiring effective treatments. However, available drugs face challenges of drug toxicity and resistance. This study investigates the prospects of plant phenolic compounds, curcumin and rosmarinic acid, as anti-leishmanial drugs against Leishmania donovani. We identified that combinations of curcumin and rosmarinic acid result in a synergistic interaction that is more effective and occurs at lower concentrations than the individual compounds. The synergistic pair functions by inducing an immune response, leading to oxidative stress for the parasite. By causing changes to the expression of iron regulatory genes, the curcumin-rosmarinic acid combination effectively chelates the essential iron required by the parasites. Although the in vitro results are interesting, further in vivo studies will be important to determine the physiological relevance of these findings. Overall, the data suggest that combinations of secondary plant metabolites may represent a potential new strategy for managing visceral leishmaniasis.
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BibTeX
@article{moore2026stagedependent,
title = {{Stage-dependent activity of curcumin-rosmarinic acid against Leishmania donovani: Synergy in amastigotes}},
author = {Christine Achiaa Antwi Moore and Jacob Kwaku Donkor and Lauve Rachel Tchokouaha Yamthe and Calvin Tiengwe and Theresa Manful Gwira},
journal = {PLOS Neglected Tropical Diseases},
year = {2026},
month = nov,
doi = {10.1371/journal.pntd.0014844},
url = {https://journals.plos.org/plosntds/article?id=10.1371/journal.pntd.0014844},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Stage-dependent activity of curcumin-rosmarinic acid against Leishmania donovani: Synergy in amastigotes
AU - Christine Achiaa Antwi Moore
AU - Jacob Kwaku Donkor
AU - Lauve Rachel Tchokouaha Yamthe
AU - Calvin Tiengwe
AU - Theresa Manful Gwira
PY - 2026
DA - 2026/11/02
JO - PLOS Neglected Tropical Diseases
DO - 10.1371/journal.pntd.0014844
UR - https://journals.plos.org/plosntds/article?id=10.1371/journal.pntd.0014844
AB - Background: Leishmania donovani causes visceral leishmaniasis, a severe and fatal parasitic disease that affects the world’s most impoverished populations. Iron metabolism is fundamental in parasite survival and host immunity. In this study, we investigated the potential use of iron-chelating compounds to inhibit intracellular L. donovani through host regulation of iron metabolism and macrophage activation. Methods: Four phenolic compounds (curcumin, rosmarinic acid, apigenin, and hesperidin) were screened individually and in fixed-ratio combinations against L. donovani promastigotes and intracellular amastigotes cultured in RAW 264.7 murine macrophages. Drug interactions were assessed using the overall mean fractional inhibitory concentration index (x―ƩFICI) averaged across four fixed ratios. Mechanistic approaches involved measuring intracellular iron, reactive oxygen species (ROS) and nitrite production, macrophage cytokine profiles, and iron-regulatory gene expression. Results: The Curcumin-rosmarinic acid (Cur-Ros) combination exhibited stage-dependent activity: additive effects against promastigotes (x―ƩFICI = 0.93) but synergistic effects, though close to the threshold, against intracellular amastigotes (x―ƩFICI = 0.49), with selectivity indexes (SI) ≥10. Treatments enhanced pro-inflammatory macrophage activation characterized by increased secretion of Tumor Necrosis Factor-alpha (TNF-α) and Monocyte chemoattractant protein-1 (MCP-1). There were decreased interleukin-10 (IL-10) levels, enhanced ROS and nitrite production, and reduced intracellular iron availability. Gene expression analysis indicated upregulation of NRAMP1 (SLC11A1, a phagosomal divalent metal transporter) and downregulation of ferritin, consistent with altered iron homeostasis. Conclusions: In this study, curcumin-rosmarinic acid combinations inhibited growth of intracellular L. donovani amastigotes synergistically, correlating with macrophage activation and altered iron homeostasis. These findings identify curcumin-rosmarinic acid as a synergistic combination warranting further investigation with appropriate formulation and in vivo validation. Author summary: Leishmaniasis remains a worldwide health threat requiring effective treatments. However, available drugs face challenges of drug toxicity and resistance. This study investigates the prospects of plant phenolic compounds, curcumin and rosmarinic acid, as anti-leishmanial drugs against Leishmania donovani. We identified that combinations of curcumin and rosmarinic acid result in a synergistic interaction that is more effective and occurs at lower concentrations than the individual compounds. The synergistic pair functions by inducing an immune response, leading to oxidative stress for the parasite. By causing changes to the expression of iron regulatory genes, the curcumin-rosmarinic acid combination effectively chelates the essential iron required by the parasites. Although the in vitro results are interesting, further in vivo studies will be important to determine the physiological relevance of these findings. Overall, the data suggest that combinations of secondary plant metabolites may represent a potential new strategy for managing visceral leishmaniasis.
SN - 1935-2735
ER -