Coping with Stress and the Emergence of Multidrug Resistance in Fungi

The incidence of invasive fungal infections poses a serious global health threat, killing nearly 1.4 million people a year—a number comparable to deaths from tuberculosis. Factors that contribute to this disease burden and high mortality include insufficient diagnostics and treatment, and the increasing numbers of individuals with immune system defects who are particularly susceptible to fungal pathogens [1]. Because of the high risk of fungal infections in immunocompromised individuals—e.g., low–birth-weight neonates or patients undergoing organ transplantation or chemotherapy—it has become common medical practice to utilize antifungal prophylaxis in these patients during immunosuppression [2–4]. However, the expanding use of antifungal drugs has been associated with increasing incidence of antifungal drug resistance resulting from inherently less sensitive species and/or acquisition of drug class–specific resistance mechanisms [5]. Most alarming in recent years, multidrug-resistant strains of certain Candida species have emerged that are resistant to azoles and echinocandins, the two most widely used classes of antifungal drugs [6,7]. In this article we explore the notion that frequent and prolonged exposures of fungal cells to antifungal drugs activate fungal stress responses, which both support the short-term cellular adaptation to the drugs [8,9] and promote genetic instability to facilitate the emergence of stable drug resistant mutants refractory to therapy [9,10], including multidrug-resistant (MDR) strains (Fig. 1). Antifungal drug-induced stress has been associated with genetic instability in such distantly related fungi as Candida and Cryptococcus [11,12], suggesting that it is a broadly conserved phenomenon. In this article, we focus on drug resistance in Candida spp. because of its clinical significance, especially with the development of emerging multidrug resistance, and because mechanisms of drug resistance and stress-associated genetic instability are best studied in Candida, both in the clinic and in the lab.