Voacamine alters Leishmania ultrastructure and kills parasite by poisoning unusual bi-subunit topoisomerase IB.

Abstract

Indole alkaloids possess a large spectrum of biological activities including anti-protozoal action. Here we report for the first time that voacamine, isolated from the plant Tabernaemontana coronaria, is an antiprotozoal agent effective against a large array of trypanosomatid parasites including Indian strain of Leishmania donovani and Brazilian strains of Leishmania amazonensis and Trypanosoma cruzi. It inhibits the relaxation activity of topoisomerase IB of L. donovani (LdTop1B) and stabilizes the cleavable complex. Voacamine is probably the first LdTop1B-specific poison to act uncompetitively. It has no impact on human topoisomerase I and II up to 200μM concentrations. The study also provides a thorough insight into ultrastructural alterations induced in three kinetoplastid parasites by a specific inhibitor of LdTop1B. Voacamine is also effective against intracellular amastigotes of different drug unresponsive field isolates of Leishmania donovani obtained from endemic zones of India severely affected with visceral leishmaniasis. Most importantly, this is the first report demonstrating the efficacy of a compound to reduce the burden of drug resistant parasites, unresponsive to SAG, amphotericin B and miltefosine, in experimental BALB/c mice model of visceral leishmaniasis. The findings cumulatively provide a strong evidence that voacamine can be a promising drug candidate against trypanosomatid infections.

• Authors: Somenath Roy Chowdhury, Ashish Kumar, Joseane Lima Prado Godinho, Sara Teixeira De Macedo Silva, Aline Araujo Zuma, Sourav Saha, Neha Kumari, Juliany Cola Fernandes Rodrigues, Shyam Sundar, Jean-Claude Dujardin, Syamal Roy, Wanderley De Souza, Sibabrata Mukhopadhyay, Hemanta K Majumder
• Journal: Biochemical pharmacology (Biochem Pharmacol) Vol. 138 Pg. 19-30 (08 15 2017) ISSN: 1873-2968 [Electronic] England
• PMID: 28483460 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2017 Elsevier Inc. All rights reserved.

Chemical References

• Antiprotozoal Agents
• Protein Subunits
• Recombinant Proteins
• Topoisomerase I Inhibitors
• voacamine
• Ibogaine
• DNA Topoisomerases, Type I

Topics

• Animals
• Antiprotozoal Agents (administration & dosage, isolation & purification, pharmacology, therapeutic use)
• Cell Shape (drug effects)
• DNA Topoisomerases, Type I (chemistry, genetics, metabolism)
• Dose-Response Relationship, Drug
• Drug Resistance, Multiple
• Enzyme Stability (drug effects)
• Female
• Ibogaine (administration & dosage, analogs & derivatives, isolation & purification, pharmacology, therapeutic use)
• Leishmania donovani (drug effects, enzymology, growth & development, ultrastructure)
• Leishmania mexicana (drug effects, enzymology, growth & development, ultrastructure)
• Leishmaniasis, Visceral (drug therapy, parasitology)
• Lethal Dose 50
• Mice, Inbred BALB C
• Microscopy, Electron, Scanning
• Microscopy, Electron, Transmission
• Plant Bark (chemistry)
• Protein Subunits (antagonists & inhibitors, genetics, metabolism)
• Recombinant Proteins (chemistry, metabolism)
• Tabernaemontana (chemistry)
• Topoisomerase I Inhibitors (administration & dosage, isolation & purification, pharmacology, therapeutic use)
• Trypanosoma cruzi (drug effects, enzymology, growth & development, ultrastructure)