The A395T Mutation in ERG11 Gene Confers Fluconazole Resistance in Candida tropicalis Causing Candidemia

Abstract

The mechanism of fluconazole resistance in Candida tropicalis is still unclear. Recently, we isolated a fluconazole-resistant strain of C. tropicalis from the blood specimen of a patient with candidemia in China. In vitro antifungal susceptibility of the isolate was determined by using CLSI M27-A3 and E-test methods. The sequence of ERG11 gene was then analyzed, and the three-dimensional model of Erg11p encoded by ERG11 gene was also investigated. The sequencing of ERG11 gene revealed the mutation of A395T in this fluconazole-resistant isolate of C. tropicalis, resulting in the Y132F substitution in Erg11p. Sequence alignment and three-dimensional model comparison of Erg11ps showed high similarity between fluconazole-susceptible isolates of C. tropicalis and Candida albicans. The comparison of the three-dimensional models of Erg11ps demonstrated that the position of the Y132F substitution in this isolate of C. tropicalis is identical to the isolate of C. albicans with fluconazole resistance resulting from Y132F substitution in Erg11p. Hence, we ascertain that the Y132F substitution of Erg11p caused by A395T mutation in ERG11 gene confers the fluconazole resistance in C. tropicalis.

Acquired multi-azole resistance in Candida tropicalis during persistent urinary tract infection in a dog

“…Reports of clinical isolates of C. tropicalis showing reduced susceptibility to azoles have multiplied in recent years but, however, there is still little information concerning the molecular mechanisms leading to antifungal resistance in this species [10] , [11] , [13] , [14] , [15] . This lack of information is particularly evident in the veterinary setting, where detailed molecular characterization of fungal isolates is still uncommon.…”

“…Nevertheless, the first azole-resistant isolate detected had a wild-type ERG3 sequence. In addition, different mutations in the ERG11 gene have been described, but only a few of them have been clearly associated with in vitro and in vivo resistance to azoles [10] , [13] , [14] , [15] . Notably, all pre- and post-azole treatment isolates from this case report had the same silent point mutations in the coding region of ERG11 and, therefore, a role of these mutations in multi-azole resistance seems unlikely.…”

Azole Antifungal Resistance in Candida albicans and Emerging Non-albicans Candida Species

“…Homozygous replacement of the wild-type C. tropicalis ERG11 with the truncated clinical variant, with or without the associated clinical ERG3 mutation, resulted in high-level fluconazole resistance in a fluconazole-susceptible reference strain of C. tropicalis . Additionally, an ERG11 mutation resulting in decreased fluconazole susceptibility due to the amino acid substitution Y132F, has been well characterized in C. albicans and was recently observed in a fluconazole-resistant C. tropicalis isolate from a patient with candidemia (Tan et al, 2015). …”

Fluconazole resistance in <em>Candida</em> species: a current perspective

“… 31 , 32 , 49 The point mutation Y132F has also been noted in a single resistant isolate of C. tropicalis . 50 Additionally, a single C. tropicalis isolate which contained a truncated Erg11p resulting from a deletion mutation and led to high-level fluconazole resistance was identified. 51 A single instance of an ERG11 mutation has been reported in C. glabrata ; a clinical isolate containing a missense mutation produced no membrane ergosterol and had high resistance to fluconazole.…”