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Antimicrobial Agents and Chemotherapy, March 2002, p. 787-796, Vol. 46, No. 3
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.3.787-796.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Relationship between Chloroquine Toxicity and Iron Acquisition in Saccharomyces cerevisiae

Lyndal R. Emerson,1 Martin E. Nau,2 Rodger K. Martin,3 Dennis E. Kyle,3 Maryanne Vahey,4 and Dyann F. Wirth1*

Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, Massachusetts,1 Henry M. Jackson Foundation for the Advancement of Military Medicine, Rockville, Maryland,2 Division of Experimental Therapeutics ,3 Division of Retrovirology, Walter Reed Army Institute of Research, Washington, D.C.4

Received 30 May 2001/ Returned for modification 6 June 2001/ Accepted 20 November 2001

Chloroquine is one of the most effective antimalarials, but resistance to it is becoming widespread. However, we do not fully understand either the drug's mode of action or the mechanism of resistance. In an effort to expand our understanding of the mechanism of action and resistance associated with chloroquine, we used Saccharomyces cerevisiae as a model eukaryotic system. To aid in the discovery of potential drug targets we applied the transcriptional profiling method to identify genes transcriptionally responsive to chloroquine treatment in S. cerevisiae. Among the genes that were differentially expressed with chloroquine treatment were a number of metal transporters involved in iron acquisition (SIT1, ARN2, ARN4, and SMF2). These genes exhibit similar expression patterns, and several are known to be regulated by AFT1, a DNA binding protein, which responds to iron levels in the cell. We investigated the role of chloroquine in iron metabolism by using a variety of approaches, including pharmacological, genetic, and biochemical techniques. For these experiments, we utilized yeast lacking the major iron uptake pathways (FET3 and FET4) and yeast deficient in SIT1, encoding the major up-regulated iron siderophore transporter. Our experiments show that yeast genetically or environmentally limited in iron availability has increased sensitivity to chloroquine in pharmacological assays and that the addition of iron rescues these cells from chloroquine killing. 55FeCl3 accumulation was inhibited in the presence of chloroquine, and kinetic analysis demonstrated that inhibition was competitive. These results are consistent with deprivation of iron as a mechanism of chloroquine killing in yeast.

* Corresponding author. Mailing address: Department of Immunology and Infectious Diseases, Harvard School of Public Health, 665 Huntington Ave., Boston, MA 02115. Phone: (617) 432-1563. Fax: (617) 432-4766. E-mail: dfwirth{at}hsph.harvard.edu.

Antimicrobial Agents and Chemotherapy, March 2002, p. 787-796, Vol. 46, No. 3
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.3.787-796.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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