Aspergillus fumigatus intrinsic fluconazole resistance is due to the naturally occurring T301I substitution in Cyp51Ap.

LEONARDELLI, FLORENCIA; MACEDO, DAIANA; DUDIUK, CATIANA; CABEZA, MATIAS; GAMARRA, SOLEDAD; GARCIA, GUILLERMO

ANTIMICROBIAL AGENTS AND CHEMOTHERAPY

AMER SOC MICROBIOLOGY

Lugar: Washington; Año: 2016

0066-4804

Aspergillus fumigatus intrinsic fluconazole-resistance has been demonstrated to be linked to the CYP51A gene, although the precise molecular mechanism has not been elucidated yet. Comparisons between A. fumigatus Cyp51Ap and Candida albicans Erg11p sequences showed differences in amino acid residues already associated with fluconazole resistance in C. albicans. The aim of this study was to analyze the role of the natural polymorphism I301 in the Aspergillus fumigatus Cyp51Ap in the intrinsic fluconazole resistance phenotype of this pathogen. The I301 residue at the A. fumigatus Cyp51Ap was replaced with a threonine (analogue to T315 at Candida albicans fluconazole-susceptible Erg11p) by changing one single nucleotide in CYP51A gene. Also a CYP51A knock out strain was obtained using the same parental strain. Both mutant?s antifungal susceptibilities were tested. The I301T mutant exhibited a lower level of resistance to fluconazole (MIC 20 ìg/ml) than the parental strain (MIC 640 ìg/ml) while no changes in MIC values were observed for other azole and non-azole based drugs. This data strongly implicate the A. fumigatus.