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Infection and Immunity, April 2001, p. 2542-2548, Vol. 69, No. 4
0019-9567/01/$04.00+0   DOI: 10.1128/IAI.69.4.2542-2548.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Virulence of a Phosphoribosylaminoimidazole Carboxylase-Deficient Candida albicans Strain in an Immunosuppressed Murine Model of Systemic Candidiasis

Matthew Donovan,1 Jon J. Schumuke,2 William A. Fonzi,3 Sheri L. Bonar,1 Karen Gheesling-Mullis,1 Gary S. Jacob,4 Vincent Jo Davisson,5 and Stanton B. Dotson2,*

Searle Research and Development, Pharmacia Company, St. Louis, Missouri 631981; Agricultural Genomics, Monsanto Company, St. Louis, Missouri 631672; Department of Microbiology and Immunology, Georgetown University, Washington, D.C. 200073; Synergy Pharmaceuticals, Sommerset, New Jersey 088734; and Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Layfayette, Indiana 47907-13335

Received 23 June 2000/Returned for modification 24 August 2000/Accepted 12 December 2000

The relative pathogenicities of three Candida albicans strains differing in the function of ADE2 (the gene encoding phosphoribosylaminoimidazole carboxylase) were evaluated in a murine candidiasis model. C. albicans strain CAI7 (ade2/ade2), previously constructed by site-specific recombination, was avirulent in immunosuppressed mice compared to the parent strain, CAF2-1, and a heterozygous ADE2/ade2 strain obtained by transforming CAI7 with a wild-type allele. The reduced virulence of CAI7 was correlated with the inability to proliferate in either synthetic medium or serum without the exogenous addition of >10 µg of adenine/ml. The loss of virulence upon site-specific disruption of the ade2 locus, and the restoration of wild-type virulence with the repair of just one ade2 allele, confirmed that the ADE2 gene and de novo purine biosynthesis were required for Candida pathogenicity. The potential of the phosphoribosylaminoimidazole carboxylase enzyme as a novel target for antifungal drug discovery is discussed.

* Corresponding author. Mailing address: Agricultural Genomics, Monsanto Company, 800 North Lindbergh Blvd., St. Louis, MO 63167. Phone: (314) 694-8271. Fax: (314) 694-3914. E-mail: stanton.b.dotson{at}monsanto.com.

Infection and Immunity, April 2001, p. 2542-2548, Vol. 69, No. 4
0019-9567/01/$04.00+0   DOI: 10.1128/IAI.69.4.2542-2548.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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