A combination of the phenolic compounds curcumin and rosmarinic acid demonstrates stage-dependent activity against the parasite Leishmania donovani, producing synergistic growth inhibition against intracellular amastigotes cultured in RAW 264.7 murine macrophages. The parasite causes visceral leishmaniasis, a severe and fatal parasitic disease that affects the world’s most impoverished populations. Because iron metabolism is fundamental to parasite survival and host immunity, investigators examined the potential of iron-chelating compounds to suppress intracellular infection through host regulation of iron metabolism and macrophage immune activation.
In the initial experimental design, four phenolic compounds—curcumin, rosmarinic acid, apigenin, and hesperidin—were screened individually and in fixed-ratio combinations. The researchers determined drug interactions by calculating the overall mean fractional inhibitory concentration index averaged across four fixed ratios. Mechanistic assessments monitored intracellular iron levels, reactive oxygen species generation, nitrite output, macrophage cytokine profiles, and the expression of key iron-regulatory genes.
The evaluation revealed distinct, stage-dependent outcomes for the curcumin-rosmarinic acid combination. While the pairing showed additive effects against promastigotes with an overall mean fractional inhibitory concentration index of 0.93, it exerted synergistic effects against intracellular amastigotes with an index of 0.49, which fell close to the synergistic threshold. In addition, the curcumin-rosmarinic acid combination maintained favorable safety margins in cellular culture, displaying selectivity indexes equal to or greater than 10 across the experimental assessments.
Mechanistic analyses demonstrated that treatment stimulated pro-inflammatory macrophage activation marked by increased secretion of tumor necrosis factor-alpha and monocyte chemoattractant protein-1. Concurrently, levels of the regulatory cytokine interleukin-10 decreased, while the production of reactive oxygen species and nitrite rose alongside a measurable reduction in intracellular iron availability. Gene expression analysis aligned with altered iron homeostasis, showing the upregulation of NRAMP1, also known as SLC11A1, a phagosomal divalent metal transporter, paired with the downregulation of ferritin storage transcripts.
The study authors conclude that the curcumin-rosmarinic acid combination synergistically inhibits the replication of intracellular Leishmania donovani amastigotes in cell culture, with the response correlating directly with pro-inflammatory macrophage activation and modulated host iron homeostasis. The investigators emphasize that these cellular findings identify curcumin and rosmarinic acid as a synergistic pairing warranting subsequent investigation, specifically noting the need for appropriate delivery formulations and validation in live animal models.
Subject of Research: Synergistic phenolic inhibition and iron regulation against intracellular Leishmania donovani
Article Title: Stage-dependent activity of curcumin-rosmarinic acid against Leishmania donovani : Synergy in amastigotes
Article References: Moore, C. A. A., Donkor, J. K., Yamthe, L. R. T., Tiengwe, C., & Gwira, T. M. (2026). Stage-dependent activity of curcumin-rosmarinic acid against Leishmania donovani: Synergy in amastigotes. PLOS Neglected Tropical Diseases, 20(11), e0014844. https://doi.org/10.1371/journal.pntd.0014844
Image Credits: AI Generated
DOI: 10.1371/journal.pntd.0014844
Keywords: Leishmania donovani, visceral leishmaniasis, curcumin, rosmarinic acid, macrophage activation, iron metabolism, NRAMP1, phenolic compounds, Stage-dependent, activity, curcumin-rosmarinic, acid
