Linking Cellular Morphogenesis with Antifungal Treatment and Susceptibility in Candida Pathogens

Abstract

Fungal infections are a growing public health concern, and an increasingly important cause of human mortality, with Candida species being amongst the most frequently encountered of these opportunistic fungal pathogens. Several Candida species are polymorphic, and able to transition between distinct morphological states, including yeast, hyphal, and pseudohyphal forms. While not all Candida pathogens are polymorphic, the ability to undergo morphogenesis is linked with the virulence of many of these pathogens. There are also many connections between Candida morphogenesis and antifungal drug treatment and susceptibility. Here, we review how Candida morphogenesis-a key virulence trait-is linked with antifungal drugs and antifungal drug resistance. We highlight how antifungal therapeutics are able to modulate morphogenesis in both sensitive and drug-resistant Candida strains, the shared signaling pathways that mediate both morphogenesis and the cellular response to antifungal drugs and drug resistance, and the connection between Candida morphology, drug resistance, and biofilm growth. We further review the development of anti-virulence drugs, and targeting Candida morphogenesis as a novel therapeutic strategy to target fungal pathogens. Together, this review highlights important connections between fungal morphogenesis, virulence, and susceptibility to antifungals.

Keywords: Antifungal drug resistance; Antifungal drugs; Candida; Fungal morphogenesis; Fungal pathogens.

Figure 1

Linking morphogenesis with antifungal drug treatment and drug resistance in Candida. (a) antifungals and their impact on morphogenesis. Candida morphogenesis can be blocked with treatment with antifungal compounds, including azoles, echinocandins, and polyenes [161,162,165,166,167]. This morphogenetic inhibition is seen even at sub-inhibitory concentrations of all three classes. (b) interactions between signalling pathways that govern morphogenesis and drug resistance. The protein kinase C (PKC)-MAPK pathway and the cAMP-PKA pathway are both involved in drug resistance and morphogenesis in Candida. Depicted are the downstream effects of PKC which regulates MAPK signalling to maintain cell wall integrity when exposed to drugs. Pkc1 has been found to regulate Cyr1 [171], which is a part of the cAMP-PKA signalling pathway, which governs filamentous growth [39]. Pkc1 is implicated in regulation of both drug resistance [172] and hyphal formation [171]. Signaling from the PKA pathway also plays a role in drug resistance via Cyr1 signaling [173,174], as well as morphogenesis [39]. Downstream transcriptional regulators of both MAPK and PKA pathways ultimately regulate morphogenesis and resistance to antifungals. Morphogenesis and filamentous growth also contribute to biofilm formation, which in turn enhances antifungal resistance. (c) transcriptional regulation of antifungal drug resistance and morphogenesis. Transcription factors such as Efg1 and Ndt80 have previously been linked to modulating expression of hyphal specific genes and promoting filamentation [95,96,97,175,176]. Both of these transcriptional regulators are also involved in drug resistance, via regulation of genes involved in drug efflux and/or ergosterol biosynthesis [176,177,178,179,180]; (d) coupling Candida morphogenesis and drug resistance through biofilm formation. Biofilms of polymorphic Candida species are typically composed of diverse cellular morphologies: hyphae, pseudohyphae and yeast [38]. Once established, these polymorphic biofilms secrete an extracellular matrix (ECM) that helps shield Candida from the external environment. Biofilms play a significant role in antifungal drug resistance by preventing antifungal penetration, sequestering antifungals, upregulating antifungal drug efflux, and metabolic regulation that limits antifungal activity [105,181,182,183]; (e) novel compounds for targeting Candida morphogenesis. New compounds are being discovered that can modulate filamentation in Candida species, and may serve as novel therapeutic strategies for treating fungal infections. Examples include drugs (i.e., filastatin), and compounds secreted by competing microbes (i.e., Bacillus safensis) that prevent filamentation, and drugs that enhances filamentation (i.e., diethylenetriaminepentaacetic acid (DTPA)).