Molecular confirmation of the linkage between Rhizopus oryzae CYP51A gene coding region and its intrinsic voriconazole and fluconazole resistance. [PublishAheadOfPrint]

Rhizopus oryzae is the most prevalent causative agent of Mucormycosis, an increasingly reported opportunistic fungal infection. These mucormycetes are intrinsically resistant to Candida- and Aspergillus-active antifungal azole drugs such as fluconazole and voriconazole, respectively. Despite of its importance, the molecular mechanisms of its intrinsic azole resistance have not been elucidated yet. The aim of this work is to establish if the Rhizopus oryzae CYP51 genes are the unique responsible for voriconazole and fluconazole intrinsic resistance in these fungal pathogens. Two CYP51 genes were identified in R. oryzae genome. We classify them as CYP51A and CYP51B based on their sequence similarity with other known fungal CYP51 genes. Later, we obtained a chimerical Aspegillus fumigatus strain harboring a functional R. oryzae CYP51A gene expressed under the regulation of wild type A. fumigatus CYP51A promoter and terminator. The mutant was selected after transformation by using a novel procedure taking advantage of the FLC-hypersusceptibility of the used A. fumigatus CYP51A deletant mutant as recipient strain. The A. fumigatus transformants harboring the R. oryzae CYP51A mimicked exactly the azole susceptibility patterns of this Mucormycete. The data presented in this work demonstrate that R. oryzae CYP51A coding sequence is the unique responsible of the R. oryzae azole susceptibility patterns.

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