Fig 1.
Mechanism of action of pentavalent antimonials in Leishmania.
Upon administration, pentavalent antimony (Sb(V)) is bioreduced to trivalent antimony (Sb(III)) within Leishmania parasites, leading to 2 primary pathways of action. Sb(III) inhibits trypanothione reductase (TryR), disrupting the parasite’s redox balance and increasing oxidative stress. Concurrently, Sb(III) affects DNA topoisomerase I activity, impairing DNA supercoiling essential for replication and transcription. Additionally, Sb(V) shows intrinsic antileishmanial activity independent of its reduction to Sb(III), further complicating the parasite’s survival. Trypanothione peroxidase (TryP) participates in detoxifying reactive oxygen species (ROS), and the inhibition of TryR enhances ROS generation, leading to further damage to parasite macromolecules, including DNA and proteins, disrupting homeostasis and contributing to parasite death.
Fig 2.
Chemical structure and proposed action mechanism of amphotericin B (AmB) against Leishmania parasites.
(A) The chemical structure of AmB, highlighting its polyene core that binds the membrane sterol ergosterol in fungi and Leishmania, as well as cholesterol in human. (B) The classical pore formation/ion channel model proposes AmB incorporated into the sterol-rich membrane, forming aqueous cytotoxic pores. (C) The ergosterol extraction mechanism is characterized by an alternative surface adsorption model and a sterol sponge model. (D) AmB-induced ROS generation, a result of auto-oxidation, further damages the parasite by targeting membrane lipids, DNA, proteins, and disrupting ion homeostasis, contributing to parasite cell death. Created with Biorender.com.
Fig 3.
Mechanisms of anti-leishmanial action by miltefosine.
(A) Miltefosine disrupts Leishmania parasites through multiple mechanisms. It interferes with lipid metabolism by integrating into parasite membranes, disrupts calcium ion homeostasis, and inhibits mitochondrial cytochrome C oxidase, collectively leading to parasite death. (B) In host cells, miltefosine modulates the immune response by affecting the PI3K/Akt signaling pathway, inducing apoptosis in infected cells, which further enhances its antiparasitic efficacy. Created with Biorender.com.
Fig 4.
Paromomycin targets the decoding center of the Leishmania cytosolic ribosome.
(A) A cryo-EM structure of the Leishmania cytosolic ribosome, showing 3 tRNAs positioned at the A-site (orange), P-site (beige), and E-site (yellow), with the mRNA in red. Paromomycin (PAR) is shown in purple, bound to the ribosomal RNA (rRNA), with ribosomal proteins in green and light blue representing the small (40S) and large (60S) subunits, respectively. (B) A close-up view of the PAR-binding pocket, highlighting its interaction with the decoding center of the ribosome, analogous to its binding site in bacterial ribosomes. (C) Paromomycin binds to the aminoacyl-tRNA recognition site on the small ribosomal subunit (40S), interfering with the translation process by causing mistranslation of the peptide chain, which compromises Leishmania growth. Created with Biorender.com.
Table 1.
Summary of key features of antileishmanial drugs of interest.