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Antimicrobial Agents and Chemotherapy, April 2008, p. 1325-1329, Vol. 52, No. 4
0066-4804/08/$08.00+0     doi:10.1128/AAC.01393-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Genomewide Screening for Genes Associated with Gliotoxin Resistance and Sensitivity in Saccharomyces cerevisiae{triangledown}

Georgios Chamilos,1 Russell E. Lewis,1,2 Gregory A. Lamaris,1 Nathaniel D. Albert,1 and Dimitrios P. Kontoyiannis1,2*

Department of Infectious Diseases, Infection Control and Employee Health, the University of Texas M. D. Anderson Cancer Center, Houston, Texas,1 University of Houston, College of Pharmacy, Houston, Texas2

Received 29 October 2007/ Returned for modification 10 November 2007/ Accepted 10 January 2008

Gliotoxin (GT) is a secondary fungal metabolite with pleiotropic immunosuppressive properties that have been implicated in Aspergillus virulence. However, the mechanisms of GT cytotoxicity and its molecular targets in eukaryotic cells have not been fully characterized. We screened a haploid library of Saccharomyces cerevisiae single-gene deletion mutants (4,787 strains in EUROSCARF) to identify nonessential genes associated with GT increased resistance (GT-IR) and increased sensitivity (GT-IS). The susceptibility of the wild-type parental strain BY4741 to GT was initially assessed by broth microdilution methods using different media. GT-IR and GT-IS were defined as a fourfold increase and decrease, respectively, in MIC, and this was additionally confirmed by susceptibility testing on agar yeast extract-peptone-glucose plates. The specificity of GT-IR and GT-IS mutants exhibiting normal growth compared with the wild-type strain was further tested in studies of their susceptibility to conventional antifungal agents, cycloheximide, and H2O2. GT-IR was associated with the disruption of genes acting in general metabolism (OPI1, SNF1, IFA38), mitochondrial function (RTG2), DNA damage repair (RAD18), and vesicular transport (APL2) and genes of unknown function (YGL235W, YOR345C, YLR456W, YGL072C). The disruption of three genes encoding transsulfuration (CYS3), mitochondrial function (MEF2), and an unknown function (YKL037W) led to GT-IS. Specificity for GT-IR and GT-IS was observed in all mutants. Importantly, the majority (69%) of genes implicated in GT-IR (6/10) and GT-IS (2/3) have human homologs. We identified novel Saccharomyces genes specifically implicated in GT-IR or GT-IS. Because most of these genes are evolutionarily conserved, further characterization of their function could improve our understanding of GT cytotoxicity mechanisms in humans.

* Corresponding author. Mailing address: Department of Infectious Diseases, Infection Control and Employee Health, Unit 402, the University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030. Phone: (713) 792-6237. Fax: (713) 745-6839. E-mail: dkontoyi{at}mdanderson.org

{triangledown} Published ahead of print on 22 January 2008.

Antimicrobial Agents and Chemotherapy, April 2008, p. 1325-1329, Vol. 52, No. 4
0066-4804/08/$08.00+0     doi:10.1128/AAC.01393-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.





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