Mechanisms of Fungal Resistance

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Abstract
The increased use of antifungal agents in recent years has resulted in the development of resistance to these drugs. The significant clinical implication of resistance has led to heightened interest in the study of antifungal resistance from different angles. In this article we discuss antifungal susceptibility testing, the mode of action of antifungals and mechanisms of resistance. Antifungals are grouped into five groups on the basis of their site of action: (i) azoles, which inhibit the synthesis of ergosterol (the main fungal sterol); (ii) polyenes, which bind to fungal membrane sterol, resulting in the formation of aqueous pores through which essential cytoplasmic materials leak out; (iii) allylamines, which block ergosterol biosynthesis, leading to accumulation of squalene (which is toxic to the cells); (iv) candins (inhibitors of the fungal cell wall), which function by inhibiting the synthesis of β 1,3-glucan (the major structural polymer of the cell wall); and (v) flucytosine, which inhibits macromolecular synthesis. Different mechanisms contribute to the resistance of antifungal agents. These mechanisms include modification of ERG11 gene at the molecular level (gene mutation, conversion and overexpression), over expression of specific drug efflux pumps, alteration in sterol biosynthesis, and reduction in the intracellular concentration of target enzymes. Approaches to prevent and control the emergence of antifungal resistance include prudent use of antifungals, treatment with the appropriate antifungal and conducting surveillance studies to determine the frequency of resistance.