**1. Introduction**

*Candida albicans* is a major fungal pathogen of humans causes superficial and deep-seated candidiasis infections [1, 2]. *C. albicans* is an opportunistic pathogen residing as a commensal in the oral cavity and gastrointestinal and urogenital tracts of many individuals [3, 4]. The severity of candidiasis ranges from superficial mucosal infections to systemic or disseminated infections. In healthy individuals, *C. albicans* is relatively harmless. However, immunocom‐

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promised patients can get disseminated candidiasis in deep tissues that are difficult to diagnose and can result in death [5, 6].Treatment involves the use of antifungals such as fluconazole, amphotericin B and caspofungin [7, 8]. However, these treatments are not always successful [9].

This chapter addresses the metabolic adaptation of isocitrate lyase (ICL1) of this fungal pathogen in humans. This topic is important for studying the pathogenicity of *C. albicans* because this medically important fungus must grow to cause infections, and to grow it must assimilate carbon. *C. albicans* can occupy various diverse niches in humans, and many of these niches contain a range of different carbon sources. The question arises whether this pathogen is able to exploit this range of carbon sources if glucose happens to be present. This would not be the case in the model yeast *Saccharomycess cerevisiae* because various forms of glucose regulation inhibit the assimilation of alternative carbon sources in this model yeast [10 - 13]. Therefore, this first compares the impact of glucose on the assimilation of alternative carbon sources in these two yeasts and then examines whether molecular mechanisms exist in *C. albicans* to promote the rapid turnover of target proteins in response to glucose. Hence, this section focusses on commensalism, *C. albicans* infections, and antifungal therapies.

*Candida* infections have been reported for virtually every tissue of the human body, and they can be classified according to different criteria [14]. Superficial infections affect the skin and mucous membranes [15]. In contrast, invasive candidiases include candidemia, acute or chronic haematogenously disseminated candidiasis (infections of the bloodstream), and deepseated infections of the internal organs [16].

*C. albicans* has evolved to become an effective commensal organism [17]. In the state of commensalism, *Candida* species live as relatively harmless members of the microflora of healthy individuals causing no discernible disease. *Candida* species are "carried" in the oral cavity, the GI tract, the anus and groin of healthy individuals, and also in the vaginal canal and vulva of healthy women [14, 18]. *Candida* is carried by the most of healthy individuals and can attain surprisingly high densities without symptoms of disease [19]. *C. albicans* is found in stools of about 50% healthy people in addition to the many bacteria that usually inhabit the GI tract [20]. The proliferation of pathogenic microorganisms such as *Candida* is inhibited partly by the growth of harmless bacteria in these niches [21]. The symbiosis of these microorganisms depends on the amount of mucus, the peristaltic behaviour of the bowel and the presence of specific host antibodies and on the capacity of these microbes to adhere to epithelial cells [20].

*C. albicans* is the most virulent *Candida* species; among the *Candida* species, *C. albicans* is the most commonly isolated yeasts from susceptible hosts [22 - 24]. Multiple risk factors play a role in increasing likelihood of *C. albicans* undergoing the transition from harmless commensal to a virulent pathogen. These risk factors include injuries or traumatic surgery; the presence of indwelling devices, such as catheters or prosthetic devices; antibiotic treatment, which reduces the competitiveness of bacterial species in host niches; and age, with new born babies or aged individuals displaying increased risk of infection [14, 24, 25].

Candidemia is defined as the isolation of *Candida* from at least one blood culture specimen. This type of infection is mainly acquired as the result of neutropenia, injuries caused by recent surgery or the presence of indwelling devices. Also the use of broad-spectrum antibiotics represents another significant risk factor [16]. *Candida* not only often infects the livers of patients during systemic candidiasis but can also thrive in their spleen, brain or kidney [26].

promised patients can get disseminated candidiasis in deep tissues that are difficult to diagnose and can result in death [5, 6].Treatment involves the use of antifungals such as fluconazole, amphotericin B and caspofungin [7, 8]. However, these treatments are not always

This chapter addresses the metabolic adaptation of isocitrate lyase (ICL1) of this fungal pathogen in humans. This topic is important for studying the pathogenicity of *C. albicans* because this medically important fungus must grow to cause infections, and to grow it must assimilate carbon. *C. albicans* can occupy various diverse niches in humans, and many of these niches contain a range of different carbon sources. The question arises whether this pathogen is able to exploit this range of carbon sources if glucose happens to be present. This would not be the case in the model yeast *Saccharomycess cerevisiae* because various forms of glucose regulation inhibit the assimilation of alternative carbon sources in this model yeast [10 - 13]. Therefore, this first compares the impact of glucose on the assimilation of alternative carbon sources in these two yeasts and then examines whether molecular mechanisms exist in *C. albicans* to promote the rapid turnover of target proteins in response to glucose. Hence, this

section focusses on commensalism, *C. albicans* infections, and antifungal therapies.

seated infections of the internal organs [16].

*Candida* infections have been reported for virtually every tissue of the human body, and they can be classified according to different criteria [14]. Superficial infections affect the skin and mucous membranes [15]. In contrast, invasive candidiases include candidemia, acute or chronic haematogenously disseminated candidiasis (infections of the bloodstream), and deep-

*C. albicans* has evolved to become an effective commensal organism [17]. In the state of commensalism, *Candida* species live as relatively harmless members of the microflora of healthy individuals causing no discernible disease. *Candida* species are "carried" in the oral cavity, the GI tract, the anus and groin of healthy individuals, and also in the vaginal canal and vulva of healthy women [14, 18]. *Candida* is carried by the most of healthy individuals and can attain surprisingly high densities without symptoms of disease [19]. *C. albicans* is found in stools of about 50% healthy people in addition to the many bacteria that usually inhabit the GI tract [20]. The proliferation of pathogenic microorganisms such as *Candida* is inhibited partly by the growth of harmless bacteria in these niches [21]. The symbiosis of these microorganisms depends on the amount of mucus, the peristaltic behaviour of the bowel and the presence of specific host antibodies and on the capacity of these microbes to adhere to epithelial cells [20].

*C. albicans* is the most virulent *Candida* species; among the *Candida* species, *C. albicans* is the most commonly isolated yeasts from susceptible hosts [22 - 24]. Multiple risk factors play a role in increasing likelihood of *C. albicans* undergoing the transition from harmless commensal to a virulent pathogen. These risk factors include injuries or traumatic surgery; the presence of indwelling devices, such as catheters or prosthetic devices; antibiotic treatment, which reduces the competitiveness of bacterial species in host niches; and age, with new born babies

Candidemia is defined as the isolation of *Candida* from at least one blood culture specimen. This type of infection is mainly acquired as the result of neutropenia, injuries caused by recent surgery or the presence of indwelling devices. Also the use of broad-spectrum antibiotics

or aged individuals displaying increased risk of infection [14, 24, 25].

successful [9].

202 Genital Infections and Infertility

*C. albicans* skin infections mostly occur in warm and moist niches such as the armpit, the perineum and skin folds. Similarly, *Candida* is a common cause of nappy (diaper) rash in infants, and it particularly affects obese and elderly adults, as well as the inframammary region of women. Itching and burning are the common symptoms of these types of infections [15]. Most women suffer from oral and vaginal infections (thrush) at least once in their life time [27]. Also, HIV and AIDS -patients suffered from oral thrush before the advent of the highly active anti-retroviral treatment (HAART), which includes a protease inhibitor that also inhibits an important virulence attribute of *C. albicans-* secreted aspartyl protease [28].

There are three main classes of clinically useful antifungal drugs: the polyenes, the azoles and the echinocandins. Amphotericin B is the main drug in the polyene family. It is thought to perturb the functionality of the fungal plasma membrane via interactions with ergosterol [29]. Unfortunately, the clinical utility of Amphotericin B is limited because it can cause nephro‐ toxicity in patients.

The azoles are an expanding family of compounds, as exemplified by the classic drug flucoa‐ zole. They target ergosterol synthesis, and hence the fungal plasma membrane [29]. Additional antifungal agents are being developed. These include triazoles such as posaconazole, ravuco‐ nazole and voriconazole. This strengthens the choice of azoles, which is the most successful antifungal class in the clinic since the late 1960s. Voriconazole is a broad spectrum drug that is fungicidal against some isolates of filamentous species [30]. Posaconazole also inhibits a broad spectrum of fungi, and has shown promising effects against Coccidioides in preclinical studies [31]. Meanwhile, ravuconazole has a long plasma half-life in humans that might improve its efficacy [32].

Echinocandins such as caspofungin, anidulafungin and micafungin target cell wall β-1 3 glucan synthesis [29]. The development of echinocandins represented a major advance in antifungal drug development because they targeted a new area of fungal cell biology -the cell wall [29]. *C. albicans* cells can become tolerant to echinocandin treatment via activation of the cell wall rescue pathway leading to elevated chitin synthesis [33].
