Azole antifungal agents are widely used to treat infections caused by
Candida spp. Antifungals belonging to this class and currently used
in patients include fluconazole (FLC), itraconazole (ITR), voriconazole
(VRC) and posaconazole (POS). Newer azoles (isavuconazole) with
are still being developed. Candida species show variable activities
against azoles. While the four major azoles show similar activities
against C. albicans, C. parapsilosis and C. tropicalis, species such as
C. krusei of C. glabrata are intrinsically less susceptible to the same
derivatives.
The acquisition of resistance to azoles in Candida spp. has been
reported and the associated mechanisms have been dissected at the
molecular level in several laboratories. These mechanisms include
mostly target alterations (mutations and overexpression of ERG11),
variations in drug efflux and more rarely sterol biosynthesis modifications.
The impact of these different mechanisms on cross-resistance to
known azoles is of interest since it could predict whether or not specific
azoles could still be used against Candida spp. exhibiting known
resistance mechanisms.
To address this question, we adopted several strategies including
expression of the diverse resistance mechanisms in heterologous hosts
and genetic dissection of resistance mechanisms in Candida spp. These
analyses were followed by MIC measurements with specific azoles. This
last approach was necessary in C. albicans, since this yeast species
usually combines several resistance mechanisms as a mode of resistance
acquisition. Our results show that, while efflux mechanisms dependent
on ABC-transporters was generating cross-resistance to all azoles, the
expression of Major Facilitators was responsible for absence of crossresistance
between specific groups of azoles (FLC/VRC vs. ITR/POS).
Target alterations yield variable degrees of cross-resistance; however,
these alterations had in general weak impact on the ITR/POS group,
even in the presence of combined ERG11 mutations. On the opposite to
C. albicans, azole resistance in C. glabrata can be acquired by a single
resistance mechanism (overexpression of ABC-transporters) and generates
cross-resistance to all azoles. Moreover, azole resistance acquisition
in this yeast species is accompanied by elevated virulence.
Therefore, extend of azole cross-resistance in Candida spp. and its clinical
relevance is a species-specific issue. Given our results, C. glabrata
appears as a yeast species requiring non-azole antifungals in therapy.