Candida Infections, Causes, Targets, and Resistance Mechanisms: Traditional and Alternative Antifungal Agents

Table 2

Resistance mechanisms of major systemic antifungal drugs. Antifungal resistance is based on different mechanisms, namely, (i) reduced drug intracellular accumulation, (ii) decreased target affinity/processivity for the drug, and (iii) counteraction of the drug effect.

Antifungal class	Genetic basis for resistance	Functional basis for resistance
Azoles	Upregulation of CDR1/CDR2 and MDR1 by point mutations in TAC1 and MRR1 transcription factors	(i) Upregulation of drug transporters
	Point mutations in ERG11	(ii) Decreased lanosterol 14-α-demethylase binding affinity for the drug
	Upregulation of ERG11 by gene duplication and transcription factor regulation	(iii) Increased concentration of lanosterol 14-α-demethylase
	Point mutations in ERG3	(iii) Inactivation of C5 sterol desaturase leading to alterations in the ergosterol synthetic pathway
Echinocandins	Point mutations in FKS1 and FKS2	(ii) Decreased glucan synthase processivity for the drug
Polyenes	Point mutations in ERG3 and ERG6	(iii) Decreased ergosterol content in cells
Nucleoside analogues	Point mutations in FCY2	(i) Inactivation of cytosine permease affecting drug uptake
	Point mutations in FCY1	(iii) Inactivation of cytosine deaminase leading to alterations in the metabolism of 5-fluorocytosine
	Point mutations in FUR1	(iii) Inactivation of uracil phosphoribosyl transferase leading to alterations in the metabolism of 5-fluorocytosine