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JAC Advance Access originally published online on February 19, 2008
Journal of Antimicrobial Chemotherapy 2008 61(5):1066-1075; doi:10.1093/jac/dkn053
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© The Author 2008. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Original research

Quercetin interferes with iron metabolism in Leishmania donovani and targets ribonucleotide reductase to exert leishmanicidal activity

Gargi Sen1, Sibabrata Mukhopadhyay2, Manju Ray1 and Tuli Biswas2,*

1 Indian Association for the Cultivation of Science, Kolkata 700032, India 2 Indian Institute of Chemical Biology, Kolkata 700032, India

Received 24 July 2007; returned 21 November 2007; revised 10 December 2007; accepted 20 January 2008

* Corresponding author. Tel: +91-33-2473-3491; Fax: +91-33-2473-0284; E-mail: tulibiswas{at}iicb.res.in

Objectives: The possibility of developing antileishmanial drugs was evaluated by intervention in the parasite's iron metabolism, utilizing quercetin (Qr) under in vivo conditions, and identifying the target of this lipophilic metal chelator against Leishmania donovani.

Methods: Interaction between Qr and serum albumin (SA) was studied by using the intrinsic fluorescence of Qr as a probe. The effect of treatment with Qr and SA on the proliferation of amastigotes was determined by evaluating splenic parasite load. Disintegration of parasites in response to combination treatment was assessed from ultrastructural analysis using a transmission electron microscope. Quenching of the tyrosyl radical of ribonucleotide reductase (RR) in treated amastigotes was detected by an electron paramagnetic resonance study.

Results: Treatment with a combination of Qr and SA increased bioavailability of the flavonoid and proved to be of major advantage in promoting the effectiveness of Qr towards the repression of splenic parasite load from 75%, P < 0.01 to 95%, P < 0.002. Qr-mediated down-regulation of RR (P < 0.05), catalysing the rate-limiting step of DNA synthesis in the pathogens, could be related to the deprivation of the enzyme of iron which in turn destabilized the critical tyrosyl radical required for its catalysing activity.

Conclusions: Results have implications for improved leishmanicidal action of Qr in combination with SA targeting RR and suggest future drug design based on interference with the parasite's iron metabolism under in vivo conditions.

Keywords: visceral leishmaniasis , amastigotes , antileishmanial drugs , molecular mechanisms , metal chelators


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