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Antimicrobial Agents and Chemotherapy, November 2008, p. 3844-3850, Vol. 52, No. 11
0066-4804/08/$08.00+0     doi:10.1128/AAC.00532-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Genomewide Expression Profiling of Cryptolepine-Induced Toxicity in Saccharomyces cerevisiae{triangledown}

Marta Rojas,1 Colin W. Wright,2 Benjamin Piña,1 and José Portugal1*

Instituto de Biologia Molecular de Barcelona, CSIC, Parc Cientific de Barcelona, E-08028 Barcelona, Spain,1 Bradford School of Pharmacy, University of Bradford, West Yorkshire, BD7 1DP, United Kingdom2

Received 24 April 2008/ Returned for modification 19 July 2008/ Accepted 7 August 2008

We have used the budding yeast Saccharomyces cerevisiae to identify genes that may confer sensitivity in vivo to the antimalarial and cytotoxic agent cryptolepine. Five S. cerevisiae strains, with different genetic backgrounds in cell permeability and DNA damage repair mechanisms, were exposed to several concentrations of cryptolepine. Cryptolepine showed a relatively mild toxicity for wild-type strains, which was augmented by either increasing cell permeability ({Delta}erg6 or ISE2 strains) or disrupting DNA damage repair ({Delta}rad52 strains). These results are compatible with the ability of cryptolepine to intercalate into DNA and thus promote DNA lesions. The effects of low concentrations of cryptolepine (20% and 40% inhibitory concentrations [IC20 and IC40]) were analyzed by comparing the gene expression profiles of treated and untreated {Delta}erg6 yeast cells. Significant changes in expression levels were observed for 349 genes (117 upregulated and 232 downregulated). General stress-related genes constituted the only recognizable functional cluster whose expression was increased upon cryptolepine treatment, making up about 20% of upregulated genes. In contrast, analysis of the characteristics of downregulated genes revealed a specific effect of cryptolepine on genes related to iron transport or acid phosphatases, as well as a significant proportion of genes related to cell wall components. The effects of cryptolepine on the transcription of iron transport-related genes were consistent with a loss of function of the iron sensor Aft1p, indicating a possible disruption of iron metabolism in S. cerevisiae. Since the interference of cryptolepine with iron metabolism is considered one of its putative antimalarial targets, this finding supports the utility of S. cerevisiae in drug-developing schemes.

* Corresponding author. Mailing address: Instituto de Biología Molecular de Barcelona, CSIC, Parc Científic de Barcelona, Baldiri Reixach, 10, E-08028 Barcelona, Spain. Phone: 34-93-403 4959. Fax: 34-93-403 4979. E-mail: jpmbmc{at}ibmb.csic.es

{triangledown} Published ahead of print on 18 August 2008.

Antimicrobial Agents and Chemotherapy, November 2008, p. 3844-3850, Vol. 52, No. 11
0066-4804/08/$08.00+0     doi:10.1128/AAC.00532-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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