Ironjustic
Sun, May-25-08, 17:15
Journal of Antimicrobial Chemotherapy 2008 61(5):1066-1075;
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 doi:10.1093/jac/dkn053
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
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
--------------------------------------------------------------
-------------------
* Corresponding author. Tel: +91-33-2473-3491; Fax:
+91-33-2473-0284; E-mail: tulibiswas@iicb.res.in
Who loves ya. Tom
Jesus Was A Vegetarian! http://tinyurl.com/2r2nkh
Man Is A Herbivore! http://tinyurl.com/a3cc3
DEAD PEOPLE WALKING http://tinyurl.com/zk9fk
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 doi:10.1093/jac/dkn053
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
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
--------------------------------------------------------------
-------------------
* Corresponding author. Tel: +91-33-2473-3491; Fax:
+91-33-2473-0284; E-mail: tulibiswas@iicb.res.in
Who loves ya. Tom
Jesus Was A Vegetarian! http://tinyurl.com/2r2nkh
Man Is A Herbivore! http://tinyurl.com/a3cc3
DEAD PEOPLE WALKING http://tinyurl.com/zk9fk