Mechanisms of Resistance to Antifungal Agents*

Antifungal therapy is an important element of patient management for acute and chronic diseases. Yet, as the global burden of fungal infections rises, treatment choices are constrained due to limited classes of antifungal agents. Furthermore, clinical management of fungal diseases is made even more tenuous by the emergence of antifungal drug resistance. More recently, the evolution of multidrug resistant organisms refractory to several different classes of antifungal agents is alarming. The resistance mechanisms responsible are largely shared by strains displaying inherently reduced susceptibility to specific antifungal agents and strains acquiring resistance during therapy. The principal molecular mechanisms are well characterized and include diminished drug-target interactions through changes in affinity and target abundance, and reduction in the intracellular level of drug through expression of high-capacity efflux pumps and biofilm formation. In some strains, high-level resistance occurs through a stepwise evolution of multiple resistance mechanisms. In recent years, a great deal has been learned about the genetic factors that regulate these mechanisms and the effectors and modulators of cellular stress, which facilitate the emergence of resistance. Understanding the primary molecular mechanisms and their regulation, along with the cellular adaptation factors that promote their emergence, provides an opportunity to develop better diagnostic tools and therapeutic strategies to overcome and prevent the emergence of antifungal resistance.