Virulence of a phosphoribosylaminoimidazole carboxylase-deficient Candida albicans strain in an immunosuppressed murine model of systemic candidiasis

The relative pathogenicities of three Candida albicans strains differing in the function of ADE2 (the gene encoding phosphoribosylaminoimidazole carbo xylase) were evaluated in a murine candidiasis model. C. albicans strain CA I7 (ade2/ade2), previously constructed by site-specific recombination, was avirulent in immunosuppressed mice compared to the parent strain, CAF2-1, a nd a heterozygous ADE2/ade2 strain obtained by transforming CAI7 with a wil d type allele. The reduced virulence of CAI7 was correlated with the inabil ity to proliferate in either synthetic medium or serum without the exogenou s addition of > 10 mug of adenine/ml. The loss of virulence upon site-speci fic disruption of the ade2 locus, and the restoration of mild-type virulenc e with the repair of just one ade2 allele, confirmed that the ADE2 gene and de novo purine biosynthesis were required for Candida pathogenicity. The p otential of the phosphoribosylaminoimidazole carboxylase enzyme as a novel target for antifungal drug discovery is discussed.