Search

The mechanisms of azole resistance in Trichosporon asahii have not yet been fully clarified. We previously showed that T. asahii has the ERG11 gene, coding lanosterol 14-α-demethylase (Erg11 protein; Erg11p), which is the primary target of azoles. A single amino acid substitution at G453R in Erg11p was found to induce changes in the affinity of this enzyme for azoles, especially fluconazole, in vitro. In the present study, we investigated the DNA sequences of the ERG11 gene using six different strains of clinically isolated T. asahii that were highly resistant to multi-azoles, including fluconazole, itraconazole, and voriconazole. All of the T. asahii strains had a point mutation (G448A) that caused a single amino acid substitution at G150S in Erg11p. This amino acid is highly conserved among major fungal pathogens. We identified a new point mutation in the ERG11 gene that is common to clinically isolated azole-resistant T. asahii strains, suggesting that this mutation is associated with the multi-azole resistance of T. asahii.

Most cases of deep-seated trichosporonosis develop in patients with neutropenia, but it has recently been reported that breakthrough infections with Trichosporon species can develop during the use of candin family of antifungal agents. This is due to the primary resistance of the causal fungus, Trichosporon asahii (T. asahii), to the candin agents. On the other hand, there has been a case report of infection with Trichosporon that presented high-level resistance to the azole family of antifungal agents. Therefore, the possibility that the frequent use of azole agents may lead to secondary resistance to these agents is a cause for concern. Since trichosporonosis is a relatively rare infectious disease, there has been no established breakpoint for this fungus to various antifungal agents, wherein we cannot precisely confirm its sensitivity or resistance to the agents. However, our experiment demonstrated one of the processes for acquired drug resistance, wherein the minimal inhibitory concentration of fluconazole for T. asahii was markedly elevated after its long-term in vitro exposure to the drug. Although the mechanisms for drug-resistance of Trichosporon species are unknown, it is supposed that they are the same as the mechanisms found in Candida and Aspergillus species, namely, modification of target molecules or decrease of access to the molecules. Since cases of trichosporonosis are likely to increase in the future, we believe that there is an urgent need to establish the breakpoint for T. asahii based on large-scale drug sensitivity tests, as well as to elucidate its drug-resistance mechanisms.

The mechanisms of azole resistance in Trichosporon asahii have not yet been fully clarified. We previously showed that T. asahii has the ERG11 gene, coding lanosterol 14-α-demethylase (Erg11 protein; Erg11p), which is the primary target of azoles. A single amino acid substitution at G453R in Erg11p was found to induce changes in the affinity of this enzyme for azoles, especially fluconazole, in vitro. In the present study, we investigated the DNA sequences of the ERG11 gene using six different strains of clinically isolated T. asahii that were highly resistant to multi-azoles, including fluconazole, itraconazole, and voriconazole. All of the T. asahii strains had a point mutation (G448A) that caused a single amino acid substitution at G150S in Erg11p. This amino acid is highly conserved among major fungal pathogens. We identified a new point mutation in the ERG11 gene that is common to clinically isolated azole-resistant T. asahii strains, suggesting that this mutation is associated with the multi-azole resistance of T. asahii.

Most cases of deep-seated trichosporonosis develop in patients with neutropenia, but it has recently been reported that breakthrough infections with Trichosporon species can develop during the use of candin family of antifungal agents. This is due to the primary resistance of the causal fungus, Trichosporon asahii (T. asahii), to the candin agents. On the other hand, there has been a case report of infection with Trichosporon that presented high-level resistance to the azole family of antifungal agents. Therefore, the possibility that the frequent use of azole agents may lead to secondary resistance to these agents is a cause for concern. Since trichosporonosis is a relatively rare infectious disease, there has been no established breakpoint for this fungus to various antifungal agents, wherein we cannot precisely confirm its sensitivity or resistance to the agents. However, our experiment demonstrated one of the processes for acquired drug resistance, wherein the minimal inhibitory concentration of fluconazole for T. asahii was markedly elevated after its long-term in vitro exposure to the drug. Although the mechanisms for drug-resistance of Trichosporon species are unknown, it is supposed that they are the same as the mechanisms found in Candida and Aspergillus species, namely, modification of target molecules or decrease of access to the molecules. Since cases of trichosporonosis are likely to increase in the future, we believe that there is an urgent need to establish the breakpoint for T. asahii based on large-scale drug sensitivity tests, as well as to elucidate its drug-resistance mechanisms.