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Metal Chelator Against Parasites
Metal Chelator Against Parasites
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
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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
