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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5219_Библиотеки_им_академика_М_И_Перельмана.pdf
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Keywords
M. Gupta et al.
Candida tropicalis · Epidemiology · Virulence · Drug resistance · Pathogenesis
Abbreviations
EMEA European Medicines Evaluation Agency
FDA Food and Drug Administration
GM-CSF Granulocyte-macrophage colony-stimulating factor
Hst5 Histatin 5
IL-17 Interleukin-17
IL-22 Interleukin-22
MPC Mononucleate phagocytic cell
NK Natural killer
PAMP Pathogen- associated molecular pattern
PMNL Polymorphonuclear leucocyte
PRR Pathogen recognition receptor
ROS Reactive oxygen species
Sap Secretory aspartyl proteases
Th1 T helper cell type one
Th2 T helper cell type two
Th17 T helper cell type seventeen
12.1 Introduction
The prevalence of infections resulting from Candida species (known as candidiasis
or moniliasis) has expanded dramatically during the last decades precisely because
of the upward push of the HIV/AIDS epidemic and the large number of patients
with immunocompromised conditions. In 1910, Candida tropicalis was discovered
in a patient with mycological bronchitis named Oidium tropicale (Castellani 1912).
In leucopenia patients, it is a common infection that travels from the bloodstream to
the organs on the periphery (Mastromarino etal. 2013). Candidemia and invasive
candidiasis diseases have historically often been linked to C. tropicalis (Antinori
etal. 2016; Zuza-Alves etal. 2017). Fungal diseases affecting internal organs occur
primarily in individuals with severe health conditions (Dermawan et al. 2018).
C. tropicalis, although closely associated with C. albicans, has a lower occurrence
rate in healthcare facility-related infections (Zuza-Alves et al. 2017). Reported
globally, C. tropicalis is the second most widespread non-albicans Candida organ-
ism associated with candidiasis patients (Furlaneto etal. 2011; Motoa etal. 2017).
In human pathology, Candida species have a crucial role as colonizers of the
mucosal membranes of the mouth and alimentary canal, as well as standard components of the skin and vagina. Under normal conditions, Candida sp. remains a nonpathogenic commensal micro organism in humans (Meersseman etal. 2009; Wang
12 Decoding the Complex Terrain of Candida tropicalis-Induced Candidiasis…
303
etal. 2016). However, C. tropicalis can cause severe oral disease, bladder infec-
tions, and nail infections (Zuza-Alves etal. 2017). The invasive candidiasis and
dermatological symptoms are primarily associated with C. tropicalis infections in
leucopenia patients (Guarana and Nucci 2018).
Among the frequently used treatment options, azoles, polyenes, and echinocan-
dins are most commonly used to treat extensive Candida infections. Flucytosine, a
pyrimidine analog, is also used to treat central nervous system candidiasis (BenAmi 2018). However, the current treatment strategies often fail due to increasing
cases of resistance or tolerance to drugs. For improving the efcacy of treatment
approaches, better methods of identifying and differentiating closely related
Candida sp. and understanding the species-specic molecular components and
mechanisms that contribute to the genesis of drug resistance are crucial (Cowen
etal. 2014). Drug resistance in C. tropicalis can be caused by a variety of mechanisms that include: (1) altered afnity for the target molecule; (2) alteration in the
target molecule structure; and (3) altered rates of drug extrusion from the cell via the
efux pumps (Grosset etal. 2016; Whaley etal. 2017). Deletions or alterations in
specic genes and change(s) in their expression can all contribute to drug resistance
mechanisms. Drug-resistant strains of C. tropicalis are associated with persistent,
continuous, and chronic fungal diseases (Garcia-Effron etal. 2008; Chong etal.
2012; Álvarez-Pérez etal. 2016). Therefore, we must improve our understanding of
the existing problem of antifungal resistance and the mechanism(s) responsible for
the observed resistance, specically concerning C. tropicalis infections.
12.2 Epidemiology
Candida infection is the most typical mycosis of the mouth and represents humans’
foremost common expediential oral infection (Vila etal. 2020). In the United States,
it was estimated that fungal infections cost about $7 billion annually (Benedict etal.
2019). Mouth infection occurs in about 6% of infants under a month old. Over 20%
of infants undergoing chemotherapy or with AIDS additionally develop critical illnesses. About three-quarters of females visiting clinics have at least one yeast infection throughout their lives. It is calculable that about 20% of females could also be
asymptomatically inhabited by fungi colonizing the duct (Sobel 2007). Esophageal
infection is the most typical passageway infection in patients with AIDS and
accounts for about 50% of all esophageal infections, typically synchronous with
alternative passageway diseases. About two-thirds of patients with AIDS and esophageal infection also have oral candidiasis.
Candida infections are quite common (Arendrup etal. 2014). C. tropicalis is the
fourth most typical cause of blood infections among United States hospital patients.
However, the incidences of blood- related fungal infections in clinics vary widely
between countries (Vallabhaneni etal. 2016). Aging, feminine sexuality, hospitalization to essential healthcare centers, and overuse of medicine are all known risk
factors associated with fungal tract infections (Hollenbach 2008; Fisher etal. 2011).
Particularly, among severely sick patients, urinary tract infections become systemic
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and are often caused by fungi like C. tropicalis (Fisher etal. 2011; Gharanfoli etal.
2019). The urogenital system is protected by vaginal microorganisms against infec-
tion (Brotman et al. 2010; Kamińska and Gajecka 2017). According to several
reports, individuals suffering from candidiasis have a higher fatality frequency than
those individuals who do not have candiduria (Bougnoux etal. 2008; Negri etal.
2012; Behzadi etal. 2015). Candidiasis is the third most common tract infection,
along with bacterial vaginosis and trichomonas. Among the most likely reasons for
vaginitis is Candida species. C. tropicalis, along with albicans species, is rapidly
being reported as the most common cause of urogenital infections (Tan etal. 2015).
According to the federal agency, 46,000 instances of healthcare-associated invasive
candidiasis occur annually in the United States. Fungemia-related mortality is estimated to exceed 70%, but can vary signicantly depending on the origin (Pappas
et al. 2018). However, increasing incidences and mortalities can be checked by
improving overall hygiene and effective disease control measures (Pappas etal.
2018). Over the years, the range of fungal species that cause aggressive candidiasis
has changed. C. tropicalis has become a joint infectious agent, but only accounts for
a small proportion of infections (Pappas etal. 2018). Among the prominent nonalbicans species, C. glabrata becomes increasingly inuential in North America and
Europe, but C. parapsilosis becomes increasingly inuential in continental Europe,
India, and Central America. Because these organisms have completely diverse susceptibilities to both the azole and echinocandin classes of antibiotics, treatment
assumptions are based on local species distribution. Fungus species vary in infectivity, with C. parapsilosis and C. krusei being less infectious than C. albicans,
C. tropicalis, and C. glabrata. The mortality rates reect this heterogeneity (Pappas
etal. 2018).
M. Gupta et al.
12.3 Immunity toCandida Infection:
Host-Pathogen Interaction
Establishing fungal infection in a highly susceptible recipient necessitates a succession of well-coordinated actions to bypass the host’s immunity. During infection,
the host immune system activates a degree of severe inammatory reaction(s), followed by a specialized lymphocyte response (Netea and Maródi 2010). Even though
all of the host systems are involved in managing mycosis, the degree of protection
that prevails is reliant on the location and severity of the developing disease (Fidel
2002; Pathakumari etal. 2020). The immunity provided by the macrophages and
polymorphonuclear leucocytes (PMNLs) is benecial in ghting against pathogenic
microorganisms, although cellular immunity is dominant until a certain point (Fidel
2002). However, the relevance of protein-mediated immunity in mycosis is disputed
(Pathakumari etal. 2020). The interplay between the host immune system and the
establishing fungal infection could result in either removal of the infectious fungi
from the immunocompromised host or a deleterious expansion of the systemic
infections such as the long-lasting connective tissue mycosis (Netea and
Maródi 2010).
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305
12.3.1 Humoral Response
The host’s rst line of protection against infection is assumed to be a physical and
anatomic obstacle restricting microbial access to the host tissue. Mucous membrane
secretions trap invading microbes and also contain peptides with antimicrobial
activity. Tissue cells secrete various cytokines and chemokines that suppress the
growth of fungal species (Fidel 2002; Pathakumari etal. 2020). Mechanistically, the
membrane produces a variety of chemicals, such as lipids, that inhibit fungal proliferation and development (Greeneld 1992). The secretion ow obstructs the adherence of fungal cells to host cell surfaces (Enwonwu and Meeks 1996). The ow and
compositional proles of the secretions can prevent oropharyngeal candidiasis in
healthy individuals by establishing a dynamic equilibrium between commensal host
ora and invading fungal sp. (De Repentigny etal. 2004; Van Der Meer etal. 2010).
In the gastrointestinal tract, various bodily factors are activated once the fungus
breaches the tissue layer and gains entry into the host tissue. One of the well-known
risk factors for moniliasis is that treatments with broad-spectrum antibiotics can
severely affect the natural gut microora (Steinbakk etal. 1990; Greeneld 1992).
The natural defense against fungal species is aided by diverse broad-spectrum
antifungal agents within the secretion. Lysozyme, lactoperoxidase histatins, calprotectin, and lactoferrin are examples (De Repentigny etal. 2004). A chelating agent
like lactoferrin ghts against mucosal microbes for complementary molecules
required for microbial growth. Additionally, it damages the ora cytomembrane and
activates intracellular lysis enzymes (De Repentigny etal. 2004). PMNLs, monocytes, tissue layer keratinocytes, and macrophages produce a heterodimeric metalbinding macromolecule called calprotectin, which inhibits fungal growth by
depriving it of metal (De Repentigny etal. 2004; Van Der Meer etal. 2010). Studies
show that calprotectin suppresses the development of fungal species in culture. The
channel’s commensal microbe ora inhibits the fungal growth through various
methods, including availability of nutrients and attachment, adverse changes in
environmental conditions, and synthesis of nephrotoxic substances (Greeneld
1992). Among the many processes accountable for fungal management by microbes,
competing for the available nourishment appears to be the most signicant
(Steinbakk etal. 1990).
A salivary protein histatin 5 (Hst5) shows fungicidal properties against many
pathogenic fungi (De Repentigny etal. 2004). Hst5 causes several negative consequences in fungi, including cell membrane damage, mitochondria destruction,
altered efux activity (like ATP and nucleotides), and cell death (Edgerton etal.
1998; De Repentigny etal. 2004).
Activation of the complement pathways is a signicant strategy of the host to
ght systemic fungal infections. Fungus-associated surface molecular patterns
(pathogen- associated molecular patterns, PAMPs) can efciently activate all three
complement cascades: classical, alternative, and mannose- binding glycoprotein.
Activation of complement proteins causes opsonization and intracellular killing of
fungal cells. The alternative complement pathway, activated by fungal membrane
components, is a signicant cause of the increase in phagocytosis of the fungal
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cells. In metabolic processes and different complement functions, the mannosebinding glycoproteins play a vital role(s). Candida can bind to each C3b and C3d
segments separately. Fungal cell metabolism processes are aided by the contact
between stimulated C3b and the complement receptor CR3. C5 also is essential for
immunity against fungal infection. When C5 is activated, C5b is formed, which aids
phagocytosis and leads to the activation and release of downstream terminal complement components (Duggan etal. 2015). Adherence to fungal surface proteins
like Pra1, Gpm1, and Gpd2 prevents recognition and alters host metabolic processes. Complement deciency impairs the host’s ability to ght off candidiasis.
Complement activation during the spread of infections also controls several communication processes (Duggan etal. 2015). PMNLs are crucial for host defense
against Candida infections (Fidel 2002; Pathakumari etal. 2020). Patients with persistent leucopenia also support this observation, or white cell abnormalities have a
higher occurrence of fungal infections like candidiasis (Demirezen etal. 2015).
A variety of specic receptors (pathogen recognition receptors or PRRs), along
with immunoglobulins and complement molecules, are categorically followed by
the PMNLs. Among the multiple mechanisms responsible for PMNL- mediated
fungal killing, the rapid generation of reactive oxygen species (ROS), or the oxidative burst, is the most prominent. To release these superoxides, the NADPH enzyme
catalyst must be assembled within the cytoplasmic membrane (Naglik etal. 2014;
Duggan etal. 2015). Further, neutrophils can delay the morphogenetic switching of
yeast cells into the hyphae. Other essential innate immune cells protecting against
Candida infection are the natural killer (NK) cells. The generation of granulocytemacrophage colony-stimulating factor (GM-CSF) is responsible for the anti-candidal activity of NK cells. NK cells secrete factors that activate mononucleate
phagocytic cells (MPCs) and PMNLs. Often these immune cells show minimal
cytotoxicity on Candida sp. The capability of MPC and PMNL to phagocytose the
fungal cells does not imply that the fungal cells are destroyed effectively. Some
fungal cells can survive and proliferate within the phagocytes and escape from
phagocytes causing the spread of infection. Disruption of phagolysosome fusion,
higher H+ ion concentration, reduced production of ROS, and morphogenetic
switching from yeast to hyphae form all contribute to protecting the invading fungus
from phagocytosis (Demirezen etal. 2015).
12.3.2 Cellular Immunity
During candidiasis infection, the cell -mediated immunity (CMI) plays a vital role
in protecting the host and determining the dynamics of host- pathogen interaction.
A Candida infection may result in mucocutaneous overgrowth and severe infection
in individuals undergoing anti-CD52 immunoglobulin therapy or with CD4 blood
illness. While T helper cell type one (Th1) protects against Candida infection, T
helper cell type two (Th2) shows insufciency to kill fungi, thereby rendering the
host cells susceptible to infection. During infection, the peripheral circulation shifts
response from Th1 to Th2 (Fidel 2002; Pathakumari etal. 2020). The PRR and
12 Decoding the Complex Terrain of Candida tropicalis-Induced Candidiasis…
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PAMP interactions can induce differentiation of Th1 into Th2 subtype(s), including
T helper cell type seventeen (Th17) (Van Der Meer etal. 2010). Assembly of antimicrobial peptides is induced by the interleukin-17 (IL-17) and interleukin-22
(IL-22) cytokines, which Th17 secretes.
Additionally, the fungal growth is also controlled by the production of β-defensins.
When IL-17 and IL-22 are released simultaneously, neutrophils are activated and
recruited to the site of infection. These activated neutrophils can rapidly clear the
fungal infection (Netea and Maródi 2010). Patients with preexisting conditions like
hyper-IgE syndrome (among other rare diseases) and deciencies in IL-17 and
IL-22 secretion are predisposed to invasive Candida infections (Van Der Meer etal.
2010). Both IL-17 and IL-22 are extremely important in regulating the fungal bur-
den and management of epithelial cell function.
12.4 Virulence Factors
Virulence factors of pathogenic fungi govern critical aspects of host invasion, like
tissue adhesion and penetration. Fungal hydrolytic enzymes, such as lipases, proteases, phospholipases, and hemolysins, constitute a good example of virulence
factor(s) (Mayer etal. 2013). Fungal proteases can degrade a wide range of host cell
proteins including albuminoid, keratin, and mucin (or mucin like glycoproteins).
Among these, the secretory aspartyl proteases (Sap), specically Sap1 to Sap10, are
the most well studied. These proteases either remain attached to the cell surface or
are released into the surrounding microenvironment (Mayer etal. 2013). Facilitating
the fungal invasion, the aspartic proteases can deteriorate the host cell membrane
and the surrounding tissue and degrade several immunological defensive proteins
(Sun etal. 2010). Moreover, increasing Sap secretion level is thought to be related
to enhanced fungus virulence and thus associated with clinical symptoms of mycosis (Sardi etal. 2013).
Phospholipases can disrupt the membrane by hydrolyzing the ester linkages of
phospholipid structures. In C. tropicalis, increased antifungal resistance is observed
in isolates with phospholipase secretion and biolm formation. Four categories of
phospholipases are thus far identied (classes A–D); however, in fungi, many members of class B are predominantly secreted into the surroundings (Deorukhkar etal.
2014; Zuza-Alves etal. 2017). Also, the secretion of phospholipases is often strain-
dependent (Cafarchia etal. 2008; Silva etal. 2009). Hemolysins represent an essential class of fungal virulence factors responsible for the destruction of red blood
cells and uptake of iron during infection. Notably, iron and other inorganic components are essential for fungal growth and the establishment of infection (Silva etal.
2009; Sardi etal. 2013). Extensive growth of Candida cells in the form of biolm is
observed on dentures and catheters in clinics and on the surface of cell membranes
(Al-Fattani and Douglas 2006; Silva etal. 2009). In a biolm, fungal cells are
embedded within an extracellular matrix, forming a complex arrangement of layered fungal laments (Mayer etal. 2013). Biolm is a fundamental virulence characteristic. It can prevent the antifungal and antimycotics from reaching into fungal
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cells through the medium, resulting in irregular antimycotic absorption, thereby
rendering fungi- resistant/ tolerant to drugs (Lohse etal. 2018; Mroczyńska and
Brillowska-Dąbrowska 2020). Studies show that the emergence of resistance to
azoles, polyene, and pyrimidine derivatives is aided by forming fungal biolms
(Sanglard 2016). Therefore, antifungals are more effective in killing fungi in yeast
form than biolms (Mayer et al. 2013). Also, an aggressive insertion of fungal
hyphae enhances the host cell entry (Silva etal. 2009). Biolm formation ability is
well known in several Candida sp., namely C. auris, C. albicans, C. glabrata,
C. parapsilosis, and C. tropicalis (Borman et al. 2016; Silva et al. 2017).
Phospholipase secretion and biolm formation are the primary virulence attributes
in C. tropicalis (Silva etal. 2017).
Esterase production has been reported in C. tropicalis, and a low esterase activity
has also been reported in C. parapsilosis. Further studies are required to establish
their roles in fungal virulence. In Candida sp., ten lipases are reported (Gácser etal.
2007). In Candida sp., lipases, essential for lipid metabolism, become crucial for
nutrient uptake, attachment to the host cell surface, and modulation of host immune
response (Sardi etal. 2013).
12.5 Treatment andDosage
C. tropicalis can cause localized systemic infections resulting in severe illnesses
and high mortalities. The standard drug medications used to cure/ treat fungus
infections include broad-spectrum antifungals like azoles or amphotericin B deoxycholate (targeting fungal sterols) (Scorzoni etal. 2017; Zuza-Alves et al. 2017).
While azoles are commonly given orally, amphotericin B requires intravenous
injections (Scorzoni etal. 2017). For topical infections, the available antifungals are
oral solution, lotion, and powder (Kothavade etal. 2010). Lotion can be directly
applied to the infection site, where the oral solution medicates oral candidiasis
infection. These antifungal agents are known to lower the phospholipase activities
of the invading fungi (Paiva and Pereira 2013). The other commonly used antifungals are Flucytosine, a pyrimidine analog, and echinocandins (targets cell wall components), namely caspofungin, micafungin, and anidulafungin (Ann Chai et al.
2010). Caspofungin can efciently target oral, esophageal, and invasive moniliasis
caused by C. tropicalis. Micafungin, compared to amphotericin B, is lot more economical. The activity of anidulafungin is similar to caspofungin and micafungin
(Ann Chai etal. 2010). Among azoles, uconazole (a solubilized antifungal) is the
most widely used antifungal approved by the Food and Drug Administration to treat
C. tropicalis infections. Oral uconazole tablets treat general mycosis, including
candidemia, tract infection, disseminated mycosis, respiratory disorder, and other
fungal infections. However, C. tropicalis cells can rapidly acquire resistance to u-
conazole; therefore, re-medication with uconazole of previously medicated
patients with recurring moniliasis is not recommended. Next-generation antimycotic azole drugs like voriconazole, ravuconazole, posaconazole, and isavuconazole
12 Decoding the Complex Terrain of Candida tropicalis-Induced Candidiasis…
have shown high activity against C. tropicalis-mediated candidiasis (Ann Chai
etal. 2010).
Fluconazole administration sometimes needs multiple doses. For the medication
of passage mycosis, the dosages vary from simply two 100mg doses on the rst
day, followed by one 100mg dose per day. However, in the case of tract infections,
the dosage varies from 50 to 200mg per day. For patients with general infection and
those undergoing bone marrow transplantations, the dosage can be as high as
400mg per day, and for patients with immunodeciency, a dosage of 200mg per
day is recommended. Therefore, a dose of 200–400mg/day is recommended in
prophylactic settings. For systemic infection, the dose is 800mg/day for the rst
day, followed by 400mg/day. 3mg/kg/day dose is recommended for children after
1year. Neonates should receive a 3–6mg/kg dose at an interval of 72h for the rst
2weeks and then at a regular gap of 48h for the next 2–4weeks and later once a day
(Charlier etal. 2006). C. tropicalis can be treated with 0.6mg/kg amphotericin B
deoxycholate or 50–70mg/kg caspofungin (Bartlett 2004). Dosage varies case-tocase basis; however, standard guidelines are in place for most scenarios. Sometimes,
a combinatorial treatment approach is also recommended.
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12.6 Drugs inClinical Use forTreating Candida Infection
12.6.1 Fluconazole
In fungi, the conversion of lanosterol to steroid alcohol, a critical step in ergosterol
synthesis, is facilitated by 14α-demethylase, a member of the cytochrome P-450
hemoprotein family (Spampinato and Leonardi 2013). Fluconazole suppresses the
ergosterol biosynthesis, an essential component of the cell membranes, thereby
increasing the membrane uidity. The fundamental reason or fungistatic activity of
uconazole is that the loss of ergosterol occurs in tandem with the accumulation of
14α-methyl sterol intermediate structures (toxic sterols) in fungi. Similarly, other
antifungals like triazoles are also fungistatic. In fact, against C. tropicalis infection,
uconazole has excellent antifungal activity. Interestingly, uconazole shows no
effect against C. krusei and is only marginally active against C. glabrata (Spampinato
and Leonardi 2013).
12.6.2 Polyenes
Polyene antifungals like amphotericin B, nystatin, and natamycin are amphiphilic.
Amphotericin B is effective against general candidiasis, nystatin against membrane
infections, and natamycin against fungal inammation (Campoy and Adrio 2017).
They can bind and sequester sterol structure within the cell membrane, making it
relatively porous. Also, the lack of specic sterol structures can directly affect the
functionality of membrane proteins (Farnoud etal. 2015).
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M. Gupta et al.
12.6.3 Echinocandins
Echinocandins represent a class of antifungals that can noncompetitively inhibit
the fungal β(1,3)--glucan synthase by targeting the Fks1 subunit. Inhibition of
Fks1 results in poor membrane development, altered diffusion, transport, and cellular damage. Candidiasis and other symptoms caused by C. tropicalis are routinely medicated with the help of echinocandins (Campoy and Adrio 2017).
Furthermore, echinocandins are licensed to treat various invasive fungal infections (Grover 2010).
12.7 Drug Resistance
In Candida sp., the fungal drug resistance is commonly attributed to the overexpression of efux pumps in the plasma membrane. For example, point mutations in
transcription factors TAC1 and MRR1 are associated with upregulating drug transporter genes like CDR1, CDR2, and MDR1 (Spampinato and Leonardi 2013; Sasani
etal. 2021) (Fig.12.1).
Azole and polyene resistance is directly associated with the ergosterol biosyn-
thetic pathway in Candida sp. (Sasani etal. 2021). Several studies have analyzed
the sterol compositions of drug-resistant isolates of C. tropicalis (Woods et al.
1974; Safe et al. 1977; Merz and Sandford 1979). Studies show mutations in
ERG3 and ERG11, upregulation of ERG11, and transcription factor UPC2 are
linked to antibiotic resistance in C. tropicalis (Castanheira etal. 2020). Alteration
of target enzyme Erg11 can prevent the binding of azoles, thereby conferring
resistance (Sasani etal. 2021) (Fig.12.1). Altered membrane sterol content affects
both azole and polyene susceptibilities (Eddouzi etal. 2013; Prasad and Singh
2013). Changes in phospholipid composition can also alter Candida sp’s drug
susceptibility proles (Chen et al. 2010). Fungal cell wall components like
β(1,3)--glucan present a unique target for broad-spectrum antifungals like echinocandins. In 2002, the Food and Drug Administration (FDA, US), as the
European Medicines Evaluation Agency (EMEA, Netherlands), licensed and
approved caspofungin acetate for treating mycosis in clinics (Denning 2002).
However, in patients with compromised immune systems, prolonged exposure to
drugs can result in poor antifungal response to echinocandins (Marak and
Dhanashree 2018). Only after 6years of being introduced into the clinics were
the rst case of resistance to micafungin and caspofungin reported in C. tropica-
lis (Pasquale etal. 2008). In Candida sp., mutations in FKS1 and FKS2 can result
in altered drug susceptibilities because of the change in the target site (Medici
and Poeta 2015). Short-term exposures to caspofungin can result in the development of acquired resistance in C. tropicalis strains, analysis of which can highlight specic mechanisms involved in altered caspofungin susceptibilities (Jensen
etal. 2013; Khan etal. 2018).
12 Decoding the Complex Terrain of Candida tropicalis-Induced Candidiasis…
311
Fig. 12.1 Partial mechanisms of azole resistance in Candida sp. Alteration in nuclear gene
expression or point mutations (TAC1, MRR1, ERG11, UPC2) can result in altered expression of
CDR1 (drug transporter) or ERG11 (lanosterol 14-α-demethylase) which can directly or indirectly
affect drug susceptibilities of Candida sp. [80]. As the representative structures, the homologybased model structures were generated using the SWISS-MODEL platform for: C. tropicalis Cdr1
and C. tropicalis Erg11. Structure of DNA was taken from Wikimedia Commons under Creative
Commons Licenses, and structure of ergosterol has been generated using the SWISS-MODEL
platform. PM plasma membrane, ER endoplasmic reticulum, N nucleus, C cytosol
12.8 Future Prospects
In identifying potential drug targets against C. tropicalis, lipid biosynthetic path-
ways can provide a suitable option. We must acknowledge that many lipid structures
and their biosynthetic enzymes are unique to fungi and, therefore, can be easily
targeted (Prasad and Singh 2013; Rollin-Pinheiro et al. 2016). We had earlier
attempted to map the lipidome of C. tropicalis and found that the lipid prole of
C. tropicalis is unique compared to the other Candida sp. (Singh etal. 2010). The
lipid proles of other major Candida sp., like C. albicans and C. auris, are well
worked out. Still, to thoroughly understand the lipid metabolism of C. tropicalis,
focused studies are required (Singh etal. 2010; Singh and Prasad 2011; Kumar etal.