Mechanisms of Antifungal Resistance
Resistance to antifungal drugs can occur through various mechanisms. These can include (a) non-synonymous point mutations within the gene encoding the target enzyme leading to alterations in the amino acid sequence, (b) increased expression of the target enzyme through increased transcription of the gene encoding it, (c) decreased concentrations of the drug within the fungal cells due to drug efflux, and (d) changes in the biosynthetic pathway resulting in reduced production of the target of the antifungal drugs.
For the azoles, each of these mechanisms has been associated with reduced susceptibility in Candida albicans, and several are associated with resistance in other Candida species. Alterations in the target enzyme (lanosterol 14-α-demethylase) due to point mutations in the encoding gene ERG11 lead to decreased susceptibilities to the azoles (Vanden Bossche et al. 1990; Parkinson et al. 1995; Lamb et al. 1997; Loffler et al. 1997; White 1997; Franz et al. 1998; Miyazaki et al. 1998; Lopez-Ribot et al. 1999; Sanglard et al. 1999; Lamb et al. 2000; Katiyar and Edlind 2001; Brun et al. 2004; Sanguinetti et al. 2005). Overexpression of the CDR1, CDR2, and MDR1 genes that encode for efflux pumps leads to azole resistance (Fling et al. 1991; Marr et al. 1998). Azole resistance has also been documented in A. fumigatus and is due to point mutations within the CYP51A gene that encodes the enzyme responsible for converting lanosterol to ergosterol (Howard et al. 2009; Vermeulen et al. 2013; Seyedmousavi et al.2014a). In isolates with environmental exposure to the azoles, tandem repeats in the promoter region along with point mutations in the gene (e.g., TR34/L98H and TR46/ Y121F/T289A) have been found and cause increased expression of CYP51A (Mellado et al. 2007).
16.4.2