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

Autor: Hemanta K. Majumder, Aline Araujo Zuma, Sara Teixeira de Macedo Silva, Neha Kumari, Sibabrata Mukhopadhyay, Ashok Kumar, Jean-Claude Dujardin, Juliany Cola Fernandes Rodrigues, Joseane Lima Prado Godinho, Syamal Roy, Somenath Roy Chowdhury, Shyam Sundar, Wanderley de Souza, Sourav Saha
Rok vydání: 2017
Předmět:
0301 basic medicine
Tabernaemontana
Trypanosoma cruzi
Leishmania mexicana
Antiprotozoal Agents
Leishmania donovani
Drug resistance
Biochemistry
Lethal Dose 50
03 medical and health sciences
0302 clinical medicine
Microscopy
Electron
Transmission
Enzyme Stability
parasitic diseases
medicine
Animals
Amastigote
Cell Shape
Biology
Pharmacology
Mice
Inbred BALB C
Miltefosine
Dose-Response Relationship
Drug
biology
Pharmacology. Therapy
Topoisomerase
Leishmania
biology.organism_classification
medicine.disease
Virology
Drug Resistance
Multiple
Recombinant Proteins
Protein Subunits
Chemistry
030104 developmental biology
Visceral leishmaniasis
DNA Topoisomerases
Type I
Ibogaine
030220 oncology & carcinogenesis
Microscopy
Electron
Scanning
Plant Bark
biology.protein
Leishmaniasis
Visceral
Female
Topoisomerase I Inhibitors
medicine.drug
Zdroj: Biochemical pharmacology
ISSN: 0006-2952
DOI: 10.1016/j.bcp.2017.05.002
Popis: 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 200 μM 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.
Databáze: OpenAIRE
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