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Antimicrobial Agents and Chemotherapy, November 2006, p. 3597-3606, Vol. 50, No. 11
0066-4804/06/$08.00+0     doi:10.1128/AAC.00653-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Unexpected Link between Iron and Drug Resistance of Candida spp.: Iron Depletion Enhances Membrane Fluidity and Drug Diffusion, Leading to Drug-Susceptible Cells{triangledown}

Tulika Prasad,1,{dagger} Aparna Chandra,2,{dagger} Chinmay K. Mukhopadhyay,2* and Rajendra Prasad1*

Membrane Biology Laboratory, School of Life Sciences,1 Special Center for Molecular Medicine, Jawaharlal Nehru University, New Delhi 110067, India2

Received 30 May 2006/ Returned for modification 15 July 2006/ Accepted 30 August 2006

Inthis study, we show that iron depletion in Candida albicans with bathophenanthrolene disulfonic acid and ferrozine 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 iron restriction. Iron uptake mutations, namely, {Delta}ftr1 and {Delta}ftr2, as well as the copper transporter mutation {Delta}ccc2, which affects high-affinity iron uptake in Candida, produced increased sensitivity to FLC compared to that of the wild type. The effect of iron depletion on drug sensitivity appeared to be independent of the efflux pump proteins Cdr1p and Cdr2p. We found that iron deprivation led to lowering of membrane ergosterol by 15 to 30%. Subsequently, fluorescence polarization measurements also revealed that iron-restricted Candida cells displayed 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.

* Corresponding author. Mailing address for Chinmay K. Mukhopadhyay: Special Centre for Molecular Medicine, Jawaharlal Nehru University, New Mehrauli Road, New Delhi 110067, India. Phone: 91-11-26704509. Fax: 91-11-26717081. E-mail: mukhopc{at}yahoo.com. Mailing address for Rajendra Prasad: School of Life Sciences, Jawaharlal Nehru University, New Mehrauli Road, New Delhi 110067, India. Phone: 91-11-26704509. Fax: 91-11-26717081. E-mail: rp47{at}hotmail.com.

{triangledown} Published ahead of print on 5 September 2006.

{dagger} T.P. and A.C. contributed equally to this work.

Antimicrobial Agents and Chemotherapy, November 2006, p. 3597-3606, Vol. 50, No. 11
0066-4804/06/$08.00+0     doi:10.1128/AAC.00653-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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