*Review* **Role of Cellular Metabolism during** *Candida***-Host Interactions**

**Aize Pellon 1,\*, Neelu Begum 1, Shervin Dokht Sadeghi Nasab 1, Azadeh Harzandi 1, Saeed Shoaie 1,2 and David L. Moyes 1,\***


**Abstract:** Microscopic fungi are widely present in the environment and, more importantly, are also an essential part of the human healthy mycobiota. However, many species can become pathogenic under certain circumstances, with *Candida* spp. being the most clinically relevant fungi. In recent years, the importance of metabolism and nutrient availability for fungi-host interactions have been highlighted. Upon activation, immune and other host cells reshape their metabolism to fulfil the energy-demanding process of generating an immune response. This includes macrophage upregulation of glucose uptake and processing via aerobic glycolysis. On the other side, *Candida* modulates its metabolic pathways to adapt to the usually hostile environment in the host, such as the lumen of phagolysosomes. Further understanding on metabolic interactions between host and fungal cells would potentially lead to novel/enhanced antifungal therapies to fight these infections. Therefore, this review paper focuses on how cellular metabolism, of both host cells and *Candida*, and the nutritional environment impact on the interplay between host and fungal cells.

**Keywords:** immunometabolism; metabolism; macrophages; epithelial cells; glycolysis; glucose; moonlighting proteins; *Candida albicans*

### **1. Introduction**

Fungal microorganisms inhabiting the human body, namely the mycobiota, constitute an essential part of the microbiota, despite their relatively low number compared to their bacterial counterparts [1,2]. Commensal fungi, either being permanent or transient colonisers, populate the skin and mucosae covering the oral cavity and the respiratory, gastrointestinal, and genitourinary tracts. Unsurprisingly, different genera governing each body site, including *Candida* (oral cavity and gut), *Malassezia* (skin), *Saccharomyces* (gut) or *Eremothecium* (lung) [3–5]. Remarkably, many of these genera, as well as other species present in our environment, are pathobionts, capable of becoming pathogenic when host immunity or tissue microenvironment changes.

Among fungal pathogens, *Candida* spp., and specifically *C. albicans*, remain the most clinically relevant fungi, causing a wide range of infections in humans from superficial to systemic candidiasis [6]. The emergence of antifungal drug resistance in *C. albicans*, as well as the increasing prevalence of infections by other *Candida* species that are intrinsically resistant to available drugs (e.g., *Candida auris*) [7], highlights the importance of finding novel therapeutic strategies to deal with these infections.

In the last couple of decades, the importance of the nutritional environment and metabolism of both host and pathogens during infectious processes has been highlighted [8]. The presence or abundance of certain metabolites, including simple carbohydrates such as glucose or galactose, modulates cellular responses of both pathogen and host, therefore being essential factors during their interactions. The stress derived from the interaction

**Citation:** Pellon, A.; Begum, N.; Sadeghi Nasab, S.D.; Harzandi, A.; Shoaie, S.; Moyes, D.L. Role of Cellular Metabolism during *Candida*-Host Interactions. *Pathogens* **2022**, *11*, 184. https://doi.org/ 10.3390/pathogens11020184

Academic Editor: Jeniel Nett

Received: 12 October 2021 Accepted: 26 January 2022 Published: 28 January 2022

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**Copyright:** © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

with the other organisms often leads to metabolic reprogramming that supports immune responses on one side and pathogenic/commensal growth on the other.

This review paper aims to explore the current knowledge regarding the role of host metabolism in the control of innate immune responses to fungal microbes on one side, and the importance of *C. albicans* metabolism for commensalism and virulence on the other. We will also highlight how metabolism modulates the biology of both host and fungal cells during their interactions, and the emerging strategies to develop novel therapeutic tools.

### **2. Immunometabolism: Feeding Immune Responses in the Host**

During the last two decades, an increasing body of evidence has identified the key role of cellular metabolism in developing immune responses, either enhancing (contributing to pathogen clearance) or diminishing (contributing to tolerogenic states) them. Thus, a new research field termed immunometabolism developed to delve into the control of immunity driven by metabolic processes [9]. Metabolic regulation of immunity has been described in both adaptive (e.g., T cells) [10] and innate (e.g., macrophages) [11] cells. Both types of cells show a wide spectrum of metabolic profiles upon activation with different stimuli. Since host immunometabolism has been extensively reviewed in recent years, we will focus on innate immunity, giving a general overview of how metabolic reprograming occurs and the modulation of immune responses by metabolites and metabolic enzymes.

### *2.1. Metabolic Reprogramming in Immune and Non-Immune Cells*

Interaction of innate immune cells, such as macrophages and monocytes, with different microorganisms leads to metabolic shifts on which their responses rely. These responses are either boosted or decreased to promote infection clearance or microbial tolerance, respectively. Since there is a great diversity of microbial structures (e.g., pathogen-associated molecular patterns (PAMPs)) and of host receptors (pattern recognition receptors (PRRs)) involved in their detection, the metabolic profiles of these differently stimulated cells, along with their derived immune responses, are also very diverse [12].

Alterations in glucose uptake and metabolism are the main hallmark of metabolic shifts in innate immune cells (Figure 1A). For instance, when macrophages are challenged with bacterial lipopolysaccharide (LPS), glucose uptake and processing via aerobic glycolysis increases, that is glycolysis coupled with lactate dehydrogenase activity leading to lactic acid production in normoxic conditions. Conversely, there is decreased activity in the tricarboxylic acid (TCA) cycle and oxidative phosphorylation (OxPhos) [13]. In contrast, cells stimulated with fungal β-glucan show an increase in both aerobic glycolysis and OxPhos [14]. Shifts in cellular metabolism towards aerobic glycolysis provide cells with more rapid energy and building blocks generation, and leading to increased cytokine release, etc. [15]. In contrast, anti-inflammatory macrophages rely on aerobic respiration, completely oxidising glucose through glycolysis, the TCA cycle and OxPhos [9].

Besides glucose metabolism, other pathways are involved during metabolic reprogramming of innate immune cells [9,16]. These pathways provide energy or redox molecules, or intermediate metabolites serving as building blocks or having regulatory functions, as explained below. The pentose phosphate pathway (PPP) provides proliferative cells with metabolites needed for nucleotide synthesis, but also contributes to NADPH production. Notably, this pathway is upregulated after LPS activation of macrophages [17], which has been related to the increased reactive oxygen species (ROS) generation in these cells via NADPH oxidase [18,19]. Fatty acid synthesis (FAS) or oxidation (FAO), alongside other lipid metabolism pathways, are also differentially regulated in activated macrophages [20]. Pro-inflammatory cells use FAS and citrate accumulated due to the TCA cycle shut down to synthesise fatty acids, prostaglandins, and leukotrienes, essential molecules for signalling events, inflammation, etc. [20,21]. In contrast, since anti-inflammatory macrophages keep their TCA and OxPhos intact but lower glycolytic levels, they rely on FAO and fatty acid uptake to feed those pathways. Finally, amino acid metabolism, such as glutamine

or arginine, is key for innate immune responses, including nitric oxide production or cytokine production [9].

**Figure 1.** Immunometabolism in innate immune cells. (**A**) Challenging innate immune cells with either exogenous (LPS, β-glucan) or endogenous (IL-4) stimuli leads to metabolic reprogramming, which involves changes in pathways as glycolysis, FAO/FAS, OxPhos, etc. These shifts in metabolism provide cells with energy and building blocks to develop their functions. (**B**) Metabolic enzymes regulate immune responses at many levels, including their moonlighting functions. They can act as transcription/translation facilitators (ENO1, PKM2, GAPDH, LDH), immune receptors or activators (HK) or facilitators of immune cell migration (ENO1). bNAG, bacterial N-acetylglucosamine; ECM, extracellular matrix; ENO1, enolase 1; FAO, fatty acid oxidation; FAS, fatty acid synthesis; GAPDH, glyceraldehyde dehydrogenase; HK, hexokinase; LDH, lactate dehydrogenase; OxPhos, oxidative phosphorylation; PKM2, pyruvate kinase M2; PLG, plasminogen; PLIN, plasmin; PPP, pentose phosphate pathway; TCA, tricarboxylic acid. Created with BioRender.com (last accessed 12 January 2022).

A number of signalling pathways govern metabolic shifts in innate immune cells [22]. Among them, the activation of the transcription factor hypoxia-inducible 1α (HIF-1α) is involved in the increase in glycolytic activity observed in LPS-activated macrophages and is responsible for the expression of several immunity-related genes [23,24]. Similarly, signalling via mechanistic target of rapamycin (mTOR) is involved in promoting cholesterol and FAS, as well as sensing amino acid and glucose availability [25].

In recent years, the ability of innate immune cells to develop long-term responses has been described, adding more complexity to the biology of these types of cells [26,27]. Essentially, the term "innate immune memory" involves a wide range of phenotypes mainly observed in monocytes/macrophages that renders them more tolerogenic or reactive against a second encounter [28]. Notably, these events are intimately linked to epigenetic and metabolic reprogramming of cells [29,30], both of which are the consequence of signalling promoted by the first encounter with the microbial challenge.

Since the discovery by Otto Warburg of the metabolic shift towards aerobic glycolysis undergone by some cancer cells [31], metabolic reprogramming has been observed in many cell types, especially in a pathologic context such as cancer. Although much of the work on these shifts driven by microbes has been carried out on immune cells, non-immune cells playing paramount roles during the infectious processes undergo similar shifts. Viral infections have been shown to modulate metabolic profiles of airway epithelial cells [32] and endothelial cells [33]. Similarly, the murine bacterial pathogen *Citrobacter rodentium* promotes a decrease in carbohydrate metabolism in intestinal epithelial cells [34], whilst skin keratinocytes increase their aerobic glycolytic metabolism in response to *Staphylococcus aureus* [35]. Despite this, the consequences of these metabolic shifts on immune responses developed by these cell types are yet to be further explored.

### *2.2. Beyond Metabolic Reprogramming: Immune Regulatory Roles of Metabolic Enzymes and Metabolites*

Besides the direct impact of metabolic reprogramming on immune cell activity (e.g., energy and redox balance, metabolite catabolism/anabolism, etc.), there are other levels of regulation of immune responses in which metabolic enzymes or metabolites play a role (Figure 1B).

Some metabolic enzymes have been observed to display regulatory functions distinct from their metabolic activities. Therefore, these proteins have been termed as "moonlighting proteins". These alternative functions of metabolic enzymes can be found among diverse biological organisms and were firstly observed in microorganisms, including bacteria and fungi, such as *Candida* spp., in which they have roles in microbial cell adhesion, pathogenicity, etc. [36,37]. Notably, the capacity of these proteins to develop moonlighting functions has been conserved in mammalian cells [38].

Glycolytic enzymes, such as hexokinase, glyceraldehyde-3-phosphate dehydrogenase (GAPDH), or enolase, display these moonlighting functions in very different ways. Hexokinase, the enzyme catalysing the first step in glycolysis, is one of the main proteins upregulated upon cell activation, and its inhibition by 2-deoxyglucose (2-DG) leads to a significant reduction in pro-inflammatory marker release [17]. However, hexokinase was recently described as a new intracellular pattern recognition receptor able to bind to the bacterial peptidoglycan component N-acetylglucosamine. This binding leads to hexokinase separation from mitochondria and drives NLRP3 inflammasome activation [39]. GAPDH regulates cytokine release in both T cells [40] and monocytes [41] by directly binding to cytokine mRNA. Enolase, involved in one of the final steps of glycolysis, has been associated with monocyte binding to plasminogen, facilitating their migration [42]. Moreover, this enzyme can modulate gene expression, including *MYC* [43] and *FOXP3* [44], by directly binding to gene regulatory elements. Similarly, PKM2 (pyruvate kinase isoform M2) can act as a co-activator of Hif-1α and regulates IL-1β expression through the activation of NLRP3 and AIM2 inflammasome [45,46]. Finally, lactate dehydrogenase (LDH), the last enzyme in the aerobic glycolytic pathway converting pyruvate in lactate, is able to bind to cytokine transcripts to modulate their translation [47,48].

It is not just proteins/enzymes involved in metabolic processes that can have these alternative immune functions. Metabolites derived from central metabolic pathways, both intermediates and final products, have been shown to modify protein function/structure and in that way modulate immune cell biology. The best-described process by which metabolites regulate immune responses is via protein post-translational modifications (PTMs). These modifications are of special relevance in the case of histones as they lead to changes in the expression of a wide range of genes—the field of epigenetics. These histones PTMs are manifold, including acetylation, phosphorylation, deamination, and methylation among others. Of these, lysine acetylation is one the clearest examples of the link between metabolism and cell functions. Acetyl-CoA is a key metabolite used by lysine acetyltransferases as a donor to acetylate proteins, although this process can occur non-enzymatically [49]. Moreover, acetyl-CoA intracellular levels correlate with protein acetylation rates and thus, changes in the nutritional environment of cells or tissues are associated with changes in acetylation levels [50].

Besides acetylation, a great variety of histone PTMs associated with metabolism has been described to date, most of them involving short-chain fatty acids (SCFAs) such as propionate, butyrate, crotonate or succinate [51]. This process is thus tightly regulated by cellular metabolism and the nutritional environment since the level of each histone acylation depends on the concentration of their respective acyl-CoA [52]. Notably, many of these PTMs have been discovered very recently and novel forms are predicted to be found in the near future. In fact, histone lysine lactylation was recently described in both human and mouse cells [53]. The event was regulated by exogenous glucose, hypoxia, and glycolytic activity levels, all three being positively correlated with intracellular lactate levels. Specifically looking at macrophages, the authors showed that stimulation of M1 polarisation

using an acute LPS and interferon-γ challenge led to higher lactate production because of the expected shift towards aerobic glycolysis. Coupled RNA-seq and lactylation-specific ChIP-seq analyses of activated macrophages showed the modulation of gene expression by these PTMs, with pro-inflammatory genes being regulated at early timepoints whilst M2 profile-related gene expression was modulated during a later phase. This suggests that histone lactylation sets a gene expression "timer" that leads to homeostasis after the inflammatory burst [53].

Metabolic intermediates can also act as intra- or extracellular signals to modulate immune responses via mechanisms beyond epigenetic modifications [54,55]. The proven existence of a wide range of metabolite transporters [56] and receptors [57] has shown the potential impact of their availability on immune cell biology. Metabolite transporters facilitate metabolite uptake and secretion, highlighting the paramount relevance of the nutritional microenvironments created during, for example, inflammatory processes. The second, metabolite receptors, are usually G-protein-coupled receptors sensing metabolites and triggering intracellular signalling events, which has led to the hypothesis of some metabolites having cytokine/chemokine-like functions [54]. Moreover, some of these metabolites, such as lactate [58] or succinate [17], have been associated with functional stabilisation of such relevant proteins as HIF-1α, the master regulator linking metabolism to immunity.

### **3. Candida Metabolism: The Significance of Being Adaptable**

As commensals and opportunistic pathogens, *Candida* spp. have developed high degree of phenotypic plasticity to adapt to diverse and changing environments. Therefore, metabolism is an essential part of *Candida* survival for nutrient assimilation and pathogenicity. The virulence of *C. albicans* is related to gene expression and host immune status [59]. *Candida* genes encoding metabolic enzymes directly interact with the host mediating fungal virulence. These virulence mechanisms include yeast-hyphal morphogenesis, phenotypic switching in the opacity of cells, adhesion, secreted hydrolases, and moonlighting proteins. *Candida* metabolic flexibility and evolution emphasises the challenges in investigating metabolic divergency with particular attention to clinical and therapeutic intervention [60,61].

Carbon assimilation and its accompanying metabolic pathway plasticity has been widely explored in *C. albicans* [62]. The carbon metabolic framework, including glycolysis, the TCA cycle and gluconeogenesis, is controlled by regulatory networks based on local nutrient availability. Metabolic plasticity allows *C. albicans* to assimilate glucose and other carbon sources simultaneously, unlike *S. cerevisiae* that switches to fermentative pathway in the presence of glucose [63]. This confers fitness in survival and adaptation to *Candida* in different host niches. General control of amino acid metabolism (GCN response) has also been linked to pathogenicity and virulence attributes of *Candida* species [61,64].

### *3.1. Impact of Metabolism on Fungal Biology: From Morphogenesis to Cell Wall Synthesis*

*C. albicans* displays a remarkable metabolic plasticity, being able to grow in the presence of different carbon sources, such as glucose, fructose, or galactose (Figure 2A). However, it shows preference towards the first one and in fact, growing on glucose as the only carbon source allows the fungus to thrive in the presence of a wide range of nutritional and stress conditions [65]. The transcriptional regulators Tye7 and Gal4 are key for the catabolism of glucose and other hexoses by *C. albicans*, controlling the expression of genes involved in glycolysis, fermentation, pyruvate dehydrogenase complex (Gal4 only), or trehalose metabolism (Tye7 only) [66]. Furthermore, Tye7 assists in cohesiveness and hyphal formation in biofilms although its absence does not impact on hyphal growth in planktonic conditions [67]. Defects in Tye7 function do not have a great impact on systemic candidiasis but have a significant effect on *C. albicans* ability to colonise the gut [68]. Gal4 regulates a unique set of carbohydrate genes initiated in hypoxic conditions that are essential for pathogenicity. Fermentable carbon sources such as galactose enhance

the glycolytic pathway and minimise dependency on fermentation [66]. Interestingly, two Gal4 analogues, Rtg1 and Rtg3, have a great impact during both systemic infections and gut colonisation, although they are involved in the regulation of a broader range of cellular processes [68].

**Figure 2.** Metabolic plasticity in *Candida*. (**A**) *Candida* species are able to grow on a wide range of compounds, giving them the chance to thrive in very different environments. This metabolic plasticity is tightly regulated by a network of transcription factors that are activated depending on the nutritional requirements of the fungus. (**B**) Growing on different compounds leads to changes in *Candida*, for example cell wall structure or composition. This is of special importance when physiologically relevant nutrients, such as lactate, are present. Utilization of these metabolites by *C. albicans* remodel its cells wall increasing antifungal drug resistance. Moreover, like host cells metabolic enzymes in *Candida* display moonlighting functions associated with, for instance, cell adhesion to the ECM (GAPDH, Eno1) or host cells (Ssa1). ECM, extracellular matrix; Eno1, enolase 1; GAPDH, glyceraldehyde dehydrogenase; FIB, fibronectin; LAM, laminin; PLG, plasminogen. Created with BioRender.com (last accessed 12 January 2022).

Moreover, carbohydrate metabolism is intimately linked to *C. albicans* morphogenesis, with nutrient starvation or serum presence being among the factors inducing the yeast-tohypha transition [69,70]. Metabolic genes are regulated during hyphal growth, including Adh1, Pgk1, and Gpm1 [71]. Similarly, white and opaque *Candida* cells display different metabolic profiles, with the white phenotype being more fermentative and the opaque being more oxidative and using FAO [65]. In fact, metabolic genes including Eno1, Fba1, Pyk1, Tpi1 and Pgi1 [72], are regulated by the central morphogenetic regulator Efg1, a transcription factor related to the white-opaque transition. Efg1 expression appears to be mechanistically connected to carbon metabolism in *Candida*. In general, Efg1 is downregulated in fermentative metabolism and upregulated in oxidative metabolism involved in morphogenesis [59,73,74]. Moreover, Efg1 stimulates fermentation and suppression of respiratory metabolism, demonstrating the importance of glycolytic metabolism in controlling virulence attributes [73]. This ability allows *Candida* species to switch between opaque and white cells (fermentative metabolism) depending on the nutritional environment [74].

As well as glycolysis, other metabolic pathways have an impact on *Candida* virulence. Knockout of FAO, for example, does not prevent candidiasis but assists in systemic virulence [75,76]. Conserved GCN networks, including *GCN4* and *GCN2* genes, are vital regulators activated during amino acid starvation. They act to reduce protein translation rates and induce cellular morphogenesis in *C. albicans* [77]. *GCN4* is a master regulator that activates morphogenesis via the Ras-cAMP signalling pathway to form pseudo-hyphae and activating amino acid biosynthetic genes [77]. In addition, GCN, particularly upregulation of *GCN4* gene, is further required for efficient biofilm formation in *C. albicans* [78]. On the other hand, the arginine pathway, meanwhile, appears to be essential in *C. albicans* as mutations in this pathway caused a defect in germ tube and hyphal formation [79]. Finally, the amino sugar N-acetylglucosamine (GlcNAc), which is the main component in chitin within the fungal cell wall, stimulates cellular responses mediating virulence, comprising of yeast-hyphae transition and stress responses [80].

The cell wall protects fungal cells from the environmental stress, controls cell morphogenesis, allows for immune recognition and is essential for cell growth of *Candida* species [81]. *C. albicans* uses sugars such as glucose, mannose, and galactose to provide energy to synthesise the cell wall. Thus, metabolic regulation is important in cell wall remodelling with the main constituents being β-glucan, chitin, and an outer layer consisting of mannoproteins (mannosylated proteins) [82]. The generation of these cell wall components requires glucose via both glycolysis catabolic and gluconeogenesis biosynthetic pathways [83]. The relative proportions of these components in the cell wall changes depending on the cells' environment. For example, β-glucan in cells within biofilms is elevated compared to non-biofilms [84]. The use of carbon sources alternative to glucose have been attributed to differences in cell wall architecture, adherence, biofilm formation, resistance to antifungal drugs and responses to stress [59,85,86]. For instance, the growth of *C. albicans* on lactate led to cell wall restructuring leading to increased resistance to azoles and oxidative stress. However, fungal cells grown on lactate media showed increased pores, higher hydrophobicity, and less elastic cell walls with reduced thickness of β-glucan and chitin [85].

### *3.2. Impact of Metabolism on Candida Pathogenic Potential*

As discussed above, *Candida* species have a robust metabolism that contributes to virulence factors (Figure 2B). Like host cells, *Candida* invasion strategies include moonlighting proteins with distinct functions. These multifunctional proteins perform additional actions to their canonical biochemical function [87,88]. Owing to evolution, some moonlighting proteins can display their different functions simultaneously, whilst others alter their activity or cellular location in response to environmental changes and cell survival needs [88]. To survive within different environments in the host organism during disease progression, microbes need to use adaptable mechanisms other than common virulence features, such as adhesion molecules and hydrolytic enzymes. In *Candida* species, different moonlighting proteins can be found attached to the cell wall, and they enable microbial cells to be more flexible and adaptable in a dynamic host environment during colonisation and invasion [89]. GAPDH, usually present in the cytoplasm, may be localised in the cell surface of *C. albicans* where it facilitates cell adhesion to fibronectin and laminin, hence helping the fungal attachment to the host and initiation of candidiasis [90]. Similarly, enolase has been identified in the surface of several clinically relevant fungi, with this enzyme being involved in fungal cell adhesion via plasminogen binding (as with macrophages) and in the degradation of the extracellular matrix (ECM) [91,92]. Moreover, the intracellular chaperone Ssa1, a member of the heat shock protein 70 family, has been shown as another atypical protein with localisation in *C. albicans* cell wall. This moonlighting protein also plays a key role during colonisation of host cells as an adhesin, acting jointly with Als3 to bind to EGFR/Her2 and E-cadherin [93–95].

While for decades there have been well-known classes of anti-fungal drugs, some of them do not specifically target fungi, hence showing toxicity for mammalian cells. Therefore, there is an urgent need to develop novel drug strategies [96]. As mentioned previously, *Candida* cell functions, such as cell wall construction and adaptation to environmental stress, significantly rely on nutrient availability and the type of carbon source. Equally, antifungal drug resistance can be also modulated by the nutritional environment. Deficit of glucose as the main carbon source force *C. albicans* cells to find an alternative source and therefore changes in the downstream machinery pathways, which could result in adaptation of the cell against different stress. Previously, it has been observed the *C. albicans* growth in presence of fermentable substrate, glucose, and non-fermentable, lactate, can change cell secretome, as well as alter the cell wall structure and proteome [97,98]. These modifications affect resistance to antifungal drugs and susceptibility to stress. In fact, *C. albicans* grown in the presence of lactate was more resistant to amphotericin B, caspofungin, and tunicamycin, whilst it showed increased susceptibility to miconazole [85]. In addition to alternative carbohydrate sources, the acidity of the environment can also make *Candida* susceptible to

antifungal drugs. Growing *C. albicans* under vaginal simulated media and in the presence of acetic acid rendered it more susceptible to fluconazole. However, *C. albicans* susceptibility to fluconazole remained unchanged when some other organic acids, such as glyoxylic acid and malonic acid, were present [99]. Similarly, *C. glabrata* shows higher susceptibility in the presence of acetic acid compared to when it is just grown on glucose [100]. These examples show the importance of carbon source availability and elucidation of the role of different nutrient in the *Candida* pathogenicity and antifungal resistance, and the need for more in depth and targeted metabolic analysis on the drug efficacy to tackle the resistome problem in fungal infections.
