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In  Candida glabrata , the transcription factor CgPdr1 is involved in resistance to azole antifungals via upregulation of ATP binding cassette (ABC)-transporter genes including at least  CgCDR1 ,  CgCDR2  and  CgSNQ2 . A high diversity of GOF (gain-of-function) mutations in  CgPDR1  exists for the upregulation of ABC-transporters. These mutations enhance  C. glabrata  virulence in animal models, thus indicating that  CgPDR1  might regulate the expression of yet unidentified virulence factors. We hypothesized that CgPdr1-dependent virulence factor(s) should be commonly regulated by all GOF mutations in  CgPDR1 . As deduced from transcript profiling with microarrays, a high number of genes (up to 385) were differentially regulated by a selected number (7) of GOF mutations expressed in the same genetic background. Surprisingly, the transcriptional profiles resulting from expression of GOF mutations showed minimal overlap in co-regulated genes. Only two genes,  CgCDR1  and  PUP1  (for   P DR1   up regulated and encoding a mitochondrial protein), were commonly upregulated by all tested GOFs. While both genes mediated azole resistance, although to different extents, their deletions in an azole-resistant isolate led to a reduction of virulence and decreased tissue burden as compared to clinical parents. As expected from their role in  C. glabrata  virulence, the two genes were expressed as well  in vitro  and  in vivo . The individual overexpression of these two genes in a  CgPDR1 -independent manner could partially restore phenotypes obtained in clinical isolates. These data therefore demonstrate that at least these two  CgPDR1- dependent and -upregulated genes contribute to the enhanced virulence of  C. glabrata  that acquired azole resistance.

Contribution of CgPDR1-Regulated Genes in Enhanced Virulence of Azole-Resistant Candida glabrata