ABSTRACT Leishmania spp., the causative agents of leishmaniasis, pose significant global health threats, with visceral leishmaniasis being the most severe and fatal form. The increasing drug resistance in the treatment of leishmaniasis emphasizes the urgent need for novel therapeutic approaches. One promising strategy involves targeting essential cellular mechanisms such as nutrient acquisition, particularly iron, which is critical for energy metabolism and signal transduction. Leishmania spp. cannot synthesize heme de novo and rely on host-derived iron and heme for survival and pathogenicity. Gallium Ga(III) is an iron Fe(III)-mimetic molecule that has emerged as a promising antimicrobial agent, offering a novel approach to combat infections, mainly by replacing Fe(III) in redox enzymes thereby disrupting essential metabolic pathways and impairing microbial viability. In this study, the antiparasitic activity of Ga (III)-protoporphyrin IX (GaPPIX) was tested against Leishmania major and Leishmania infantum , both in promastigotes and intracellular amastigotes. Our results demonstrate that GaPPIX inhibits the viability of both species, specifically targeting the enzymatic activity of cytochrome c oxidase, with a higher sensitivity observed in L. major . The inhibitory effect is reversed by hemin, suggesting specificity for Leishmania heme-dependent cellular processes and a possible cytostatic action. Moreover, we found that GaPPIX can effectively synergize with miltefosine. This feature, coupled with its minimal toxicity toward human cells, makes GaPPIX a good candidate to be potentially developed as a novel anti- Leismania agent. IMPORTANCE This study is significant as it addresses a critical challenge in leishmaniasis management, namely, the increasing incidence of drug resistance and toxicity, compounded by the scarcity of effective therapeutic options. We demonstrate that GaPPIX, a heme-mimetic compound, exhibits potent antiparasitic activity against both Leishmania major and Leishmania infantum , while displaying minimal cytotoxicity toward human cells, underscoring its potential as a safe and targeted therapeutic candidate. Importantly, the ability of GaPPIX to synergize with the first-line drug miltefosine highlights its translational relevance in combination therapies, which are essential for overcoming resistance and improving treatment efficacy. Collectively, these findings advance GaPPIX as a promising approach for the development of innovative therapeutics against a neglected but globally significant disease.
Maestrini et al. (Fri,) studied this question.