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Julia Johnston¹, Jonathan Taylor¹, Surbhi Nahata¹

¹School of Pharmacy, Pacific University, Hillsboro, OR 97123, USA.

Pathogens (Basel, Switzerland)

|February 26, 2025

Abstract:

The polyamine pathway in Leishmania parasites has emerged as a promising target for therapeutic intervention, yet the functions of polyamines in parasites remain largely unexplored. Ornithine decarboxylase (ODC) and spermidine synthase (SPDSYN) catalyze the sequential conversion of ornithine to putrescine and spermidine. We previously found that Leishmania donovani Δodc and Δspdsyn mutants exhibit markedly reduced growth in vitro and diminished infectivity in mice, with the effect being most pronounced in putrescine-depleted Δodc mutants. Here, we report that, in polyamine-free media, ∆odc mutants arrested proliferation and replication, while ∆spdsyn mutants showed a slow growth and replication phenotype. Starved ∆odc parasites also exhibited a marked reduction in metabolism, which was not observed in the starved ∆spdsyn cells. In contrast, both mutants displayed mitochondrial membrane hyperpolarization. Hallmarks of apoptosis, specifically DNA fragmentation and membrane modifications, were observed in Δodc mutants incubated in polyamine-free media. These results show that putrescine depletion had an immediate detrimental effect on cell growth, replication, and mitochondrial metabolism and caused an apoptosis-like death phenotype. Our findings establish ODC as the most promising therapeutic target within the polyamine biosynthetic pathway for treating leishmaniasis.

Insights

Ornithine decarboxylase (ODC) is crucial for Leishmania parasite survival. Depleting putrescine via ODC inhibition halts parasite growth, metabolism, and induces apoptosis, making it a key therapeutic target for leishmaniasis.

Area of Science:

Parasitology
Molecular Biology
Biochemistry

Background:

The polyamine pathway is essential for Leishmania parasites but its functions are not fully understood.
Polyamines are critical for parasite growth, replication, and infectivity.
Ornithine decarboxylase (ODC) and spermidine synthase (SPDSYN) are key enzymes in polyamine biosynthesis.

Purpose of the Study:

To investigate the role of polyamines in Leishmania parasites.
To determine the specific functions of ornithine decarboxylase (ODC) and spermidine synthase (SPDSYN) in parasite survival and virulence.
To evaluate the therapeutic potential of targeting the polyamine pathway in leishmaniasis.

Main Methods:

Generation and characterization of Leishmania donovani mutants lacking ODC (Δodc) and SPDSYN (Δspdsyn).
Culturing mutants in polyamine-free media to assess growth, proliferation, and replication.
Analysis of parasite metabolism, mitochondrial function, and apoptosis markers (DNA fragmentation, membrane modifications).

Main Results:

Δodc mutants showed complete growth arrest and replication cessation in polyamine-free media.
Δspdsyn mutants exhibited slow growth and replication.
Δodc mutants displayed reduced metabolism and apoptosis-like death, while both mutants had mitochondrial hyperpolarization.

Conclusions:

Putrescine depletion severely impacts Leishmania parasite growth, replication, metabolism, and induces apoptosis.
ODC is the most critical enzyme in the polyamine pathway for parasite survival.
ODC represents a highly promising therapeutic target for treating leishmaniasis.

Read full analysis

Keywords:

Leishmania apoptosis mitochondria ornithine decarboxylase polyamines replication spermidine synthase starvation

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