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29 May 2008

The Candida albicans Ddr48 protein is essential for filamentation, stress response, and confers partial antifungal drug resistance

Leila DibBCDF, Peter HayekBCF, Helen SadekC, Berna BeyrouthyCD, Roy A. KhalafACDEF

Med Sci Monit 2008; 14(6): BR113-121 :: ID: 859029

Abstract

Background
Candida albicans is a dimorphic pathogenic fungus that causes mucosal and systemic infections. C. albicans pathogenicity is attributed to its ability to exist in different morphologic states and to respond to stress by up regulating several key genes. DDR48 is a stress-associated gene involved in DNA repair and in response to antifungal drug exposure.
Material and Method
One allele of DDR48 was knocked out by homologous recombination that inserted a marker cassette in its position. Furthermore, reintroducing DDR48 on a plasmid created a revertant strain. Strains were grown on filamentation inducing and noninducing media, subjected to an oxidative stress challenge, injected into mice to assess virulence, and assayed for antifungal susceptibility by the E-test method.
Results
DDR48 was found to be haploid insufficient and possibly essential, since only a heterozygote, but not a homozygous, null mutant was generated. The mutant was filamentation defective on all hyphal media tested including serum and corn meal agar. Discrepancies in drug resistance profiles also were present: compared with the parental strain, DDR48/ddr48 heterozygote strain was susceptible in a dose-dependent manner to itraconazole and fluconazole and susceptible to ketoconazole. The mutant also appeared to be hypersensitive to a potentially lethal hydrogen peroxide challenge. However, no reduction in virulence of the mutant was observed.
Conclusions
The present findings provide evidence that DDR48 is essential for filamentation, stress response, and possibly viability of C. albicans, making it a prime target for antifungal drug design.

Keywords: Oxidative Stress - drug effects, Microbial Sensitivity Tests, Mice, Inbred BALB C, Hyphae - growth & development, Heterozygote, Gene Deletion, Fungal Proteins - metabolism, Drug Resistance, Fungal - drug effects, Virulence, Phenotype, Culture Media, Candida albicans - pathogenicity, Antifungal Agents - pharmacology

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