Regulatory Circuitry Governing Fungal Development, Drug Resistance, and Disease

Abstract

SUMMARY Pathogenic fungi have become a leading cause of human mortality due to the increasing frequency of fungal infections in immunocompromised populations and the limited armamentarium of clinically useful antifungal drugs. Candida albicans , Cryptococcus neoformans , and Aspergillus fumigatus are the leading causes of opportunistic fungal infections. In these diverse pathogenic fungi, complex signal transduction cascades are critical for sensing environmental changes and mediating appropriate cellular responses. For C. albicans , several environmental cues regulate a morphogenetic switch from yeast to filamentous growth, a reversible transition important for virulence. Many of the signaling cascades regulating morphogenesis are also required for cells to adapt and survive the cellular stresses imposed by antifungal drugs. Many of these signaling networks are conserved in C. neoformans and A. fumigatus , which undergo distinct morphogenetic programs during specific phases of their life cycles. Furthermore, the key mechanisms of fungal drug resistance, including alterations of the drug target, overexpression of drug efflux transporters, and alteration of cellular stress responses, are conserved between these species. This review focuses on the circuitry regulating fungal morphogenesis and drug resistance and the impact of these pathways on virulence. Although the three human-pathogenic fungi highlighted in this review are those most frequently encountered in the clinic, they represent a minute fraction of fungal diversity. Exploration of the conservation and divergence of core signal transduction pathways across C. albicans , C. neoformans , and A. fumigatus provides a foundation for the study of a broader diversity of pathogenic fungi and a platform for the development of new therapeutic strategies for fungal disease.

Fluconazole impacts the extracellular matrix of fluconazole-susceptible and -resistant Candida albicans and Candida glabrata biofilms

“…An important aspect to be considered in therapy with topical or systemic antifungals is resistance to these drugs. Resistance to antifungal agents can be defined as the persistence or progression of infection after application of antimicrobial treatment [16,17]. Some studies have observed the emergence of resistant microorganisms during long-term or prophylactic treatment [18,19].…”

“…Some Candida species possess intrinsic resistance to antifungal drugs, especially to FLZ [7,10]. In contrast, secondary resistance is one that can be developed by yeasts after long periods of exposure to antifungal drugs [16]. Thus, a major concern with Candida spp.…”

A comprehensive functional portrait of two heat shock factor-type transcriptional regulators involved in Candida albicans morphogenesis and virulence

“…The yeast-to-hyphae transition is triggered by a variety of environmental stimuli including nutrient availability, temperature, pH, CO 2 and serum [9][10][11][12][13]. This process correlates with the coordinated expression of a set of hyphal-specific genes (HSGs) with roles in orchestrating hyphal development.…”

“…This process correlates with the coordinated expression of a set of hyphal-specific genes (HSGs) with roles in orchestrating hyphal development. Consequently, the transition is highly regulated and involves multiple interconnected signalling pathways, including the cyclic AMP-dependent Protein Kinase A (cAMP-PKA, regarded as playing a central role in the control of morphogenesis), the Cph1p-mediated Mitogen-Activated Protein Kinase (MAPK) and the Rim101p-mediated pH cascade pathways, all of which positively regulate hyphal development through the modulation of the activity of transcription factors to control the expression of HSGs (see [13] for a recent review). These transcription factors include (among others) Efg1p/ Flo8p, acting downstream of cAMP-PKA [14][15][16][17][18][19][20], Tec1p [21] and Ume6p [22,23].…”

Antifungal Drug Development: Challenges, Unmet Clinical Needs, and New Approaches

“…Concurrent work in the Lin labora-tory showed similar activity in a mouse model of disseminated cryptococcosis (Zhai et al 2012). Most intriguingly, Cowen and colleagues have shown that inhibitors of the molecular chaperone Hsp90, including the natural products geldanamycin and radicicol, possess potent in vitro synergy in combination with azoles and echinocandins, that this synergy extends across both C. albicans and A. fumigatus, and that it is observed in an invertebrate model of candidiasis Singh et al 2009;Shapiro et al 2011). Therefore, ongoing chemical modification of geldanamycin as a novel oncology agent offers opportunities to "repurpose" new geldanamycin analogs as adjuvants for existing antifungals.…”