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

• Published in: Biochemical pharmacology Vol. 138; pp. 19 - 30
• Main Authors: Chowdhury, Somenath Roy, Kumar, Ashish, Godinho, Joseane Lima Prado, De Macedo Silva, Sara Teixeira, Zuma, Aline Araujo, Saha, Sourav, Kumari, Neha, Rodrigues, Juliany Cola Fernandes, Sundar, Shyam, Dujardin, Jean-Claude, Roy, Syamal, De Souza, Wanderley, Mukhopadhyay, Sibabrata, Majumder, Hemanta K.
• Format: Journal Article
• Language: English
• Published: England Elsevier Inc 15.08.2017
• Subjects: Animals; Antiprotozoal Agents - administration & dosage; Antiprotozoal Agents - isolation & purification; Antiprotozoal Agents - pharmacology; Antiprotozoal Agents - therapeutic use; Cell Shape - drug effects; DNA Topoisomerases, Type I - chemistry; DNA Topoisomerases, Type I - genetics; DNA Topoisomerases, Type I - metabolism; Dose-Response Relationship, Drug; Drug Resistance, Multiple; Enzyme Stability - drug effects; Female; Ibogaine - administration & dosage; Ibogaine - analogs & derivatives; Ibogaine - isolation & purification; Ibogaine - pharmacology; Ibogaine - therapeutic use; Kinetoplastids; Leishmania donovani - drug effects; Leishmania donovani - enzymology; Leishmania donovani - growth & development; Leishmania donovani - ultrastructure; Leishmania mexicana - drug effects; Leishmania mexicana - enzymology; Leishmania mexicana - growth & development; Leishmania mexicana - ultrastructure; Leishmaniasis, Visceral - drug therapy; Leishmaniasis, Visceral - parasitology; Lethal Dose 50; Mice, Inbred BALB C; Microscopy, Electron, Scanning; Microscopy, Electron, Transmission; Plant Bark - chemistry; Protein Subunits - antagonists & inhibitors; Protein Subunits - genetics; Protein Subunits - metabolism; Recombinant Proteins - chemistry; Recombinant Proteins - metabolism; Tabernaemontana - chemistry; Topoisomerase I Inhibitors - administration & dosage; Topoisomerase I Inhibitors - isolation & purification; Topoisomerase I Inhibitors - pharmacology; Topoisomerase I Inhibitors - therapeutic use; Topoisomerase IB; Trypanosoma cruzi - drug effects; Trypanosoma cruzi - enzymology; Trypanosoma cruzi - growth & development; Trypanosoma cruzi - ultrastructure; Ultrastructure; Voacamine; Kinetoplastids; Ultrastructure; Topoisomerase IB; Voacamine
• ISSN: 0006-2952; 1873-2968
• DOI: 10.1016/j.bcp.2017.05.002

[Display omitted] 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.