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From: ironjustice on 31 Jul 2008 10:42
Unexpected Link between Iron and Drug Resistance of Candida spp.:
Iron Depletion Enhances Membrane Fluidity and Drug Diffusion,
Leading to Drug-Susceptible Cells
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Nov. 2006, p. 3597–3606 Vol.
50, No. 11

Tulika Prasad,1† Aparna Chandra,2† Chinmay K. Mukhopadhyay,2* and
Rajendra Prasad1*
Membrane Biology Laboratory, School of Life Sciences,1 and Special
Center for Molecular Medicine,2
Jawaharlal Nehru University, New Delhi 110067, India
Received 30 May 2006/Returned for modification 15 July 2006/Accepted
30 August 2006
In this study, we show that iron depletion in Candida albicans with
bathophenanthrolene disulfonic acid andferrozine as chelators enhanced
its sensitivity to several drugs, including the most common
antifungal,fluconazole (FLC).
Several other species of Candida also displayed increased sensitivity
to FLC because of ironrestriction.
Iron uptake mutations, namely, ftr1 and ftr2, as well as the copper
transporter mutation ccc2,which affects high-affinity iron uptake in
Candida, produced increased sensitivity to FLC compared to that ofthe
wild type.
The effect of iron depletion on drug sensitivity appeared to be
independent of the efflux pumpproteins Cdr1p and Cdr2p.
We found that iron deprivation led to lowering of membrane ergosterol
by 15 to30%.
Subsequently, fluorescence polarization measurements also revealed
that iron-restricted Candida cellsdisplayed a 29 to 40% increase in
membrane fluidity, resulting in enhanced passive diffusion of the
drugs.
Northern blot assays revealed that the ERG11 gene was considerably
down regulated in iron-deprived cells,which might account for the
lowered ergosterol content.
Our results show a close relationship between cellular
iron and drug susceptibilities of C. albicans.
Considering that multidrug resistance is a manifestation of
multifactorial phenomena, the influence of cellular iron on the drug
susceptibilities of Candida suggests iron as yet another novel
determinant of multidrug resistance.

0066-4804/06/$08.000 doi:10.1128/AAC.00653-06
Copyright © 2006, American Society for Microbiology. All Rights
Reserved.


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