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Fig. 12.2 Sphingolipid synthesis can be targeted to treat C. tropicalis infections. (a) Partial path-
way of GlcCer synthesis. Structure of αOH-Δ4-Δ8–9-methyl-GlcCer (d19:2/18:0 h-GlcCer),
which is the most abundant GlcCer structure in Candida sp., except few species like C. glabrata, is
depicted as a representative. (b) Structure of acylhydrazone D0 [3-bromo-N′-(3-bromo-4-
hydroxybenzylidene) benzohydrazide], which is known to inhibit GlcCer synthesis in Candida sp.,
is depicted as a representative. ‘Glc’ represents: glucosyl moiety
M. Gupta et al.
2021). Among fungal lipids, sphingolipids have emerged as an essential drug target
(Rollin-Pinheiro etal. 2016). Earlier studies have shown that hydrazine derivatives
efciently kill C. tropicalis cells (Carradori etal. 2013; Turan-Zitouni etal. 2013;
Dascalu etal. 2020; Kumar etal. 2021). A recent study has shown that hydrazine
derivatives (acylhydrazones) show anti-candidal targeting the sphingolipid metabolism, specically glucosylceramide (GlcCer) synthesis (Mor etal. 2015; Lazzarini
etal. 2018) (Fig.12.2).
However, whether hydrazine derivatives target the sphingolipid metabolism to
show antifungal activity in C. tropicalis remains to be established. Also, the fact
that acylhydrazones can potentially show synergistic activity with the established
antifungals against other Candida strains opens up a possibility that a similar effect
could be observed in C. tropicalis as well and should be tested (Lazzarini etal.
2018). Drug resistance in a growing number of mycosis patients presents chal-
lenges for clinicians. Poor diagnostics and outdated therapeutics are the signicant
contributors to our inability to treat drug- resistant pathogenic fungi, including
C. tropicalis. Several available drug medications show reduced susceptibility or
complete resistance against the infecting fungus. Recently, researchers have tried
to resolve the problem of cellular drug toxicity as well. Many developing nextgeneration antifungals show promising results with improved activity, better bioavailability, limited toxicity, and other harmful effects. Despite their adverse side
effects, some of these medications are in use because of their high antifungal
12 Decoding the Complex Terrain of Candida tropicalis-Induced Candidiasis…
313
activity. However, these drugs may take over a decade to go through all the channels for clinical approval and use. Also, to determine the true potential of these
medicines in solving the problem of fungal drug resistance, many more medical
investigations are needed. The future of treating drug- resistant Candida sp. will
depend on (1) accurate identication of closely related Candida sp. in patient samples; (2) consistency of invitro drug susceptibility testing methods; (3) developing
cost- effective broad spectrum antifungals to treat supercial infections; (4) developing species- specic antifungals for systemic infections; (5) getting rid of toxicity or any other side effect(s); (6) simple drug delivery system like oral pills; (7)
improved bioavailability; (8) understanding the exact mechanism(s) of drug susceptibilities and resistance; (9) nding the best combinatorial drug combinations;
(10) repurposing of drugs in clinical use against other infections or diseases as
potential antifungals.
12.9 Conclusions
Recently, the cases of infections caused by C. tropicalis have risen in clinics. This
fungus causes invasive candidiasis, oral mycosis, and several other types of infection. Several factors contribute to the rise of C. tropicalis infection cases. These
factors include the lack of novel and cost-effective detection assays, denitive
microbial and immune response assessment, and resistance to drug(s) used for treating these infections. Other host-related factors include preexisting patient
condition(s), extended hospital stays, and unmonitored use of a wide variety of
antibiotics. The pathogenesis of C. tropicalis arises from its ability to colonize the
host and cause substantial injury to host tissue. More targeted studies are demanded
to understand how C. tropicalis can bypass host immune defense and develop strate-
gies to evade killing by antifungals. Also, the discovery of novel broad spectrum and
C. tropicalis-specic antifungal(s) is much needed.
Acknowledgments RP and AS acknowledge the funding supported by the Department of
Biotechnology (BT/PR38505/MED/29/1513/2020), Govt. of India and Department of Science and
Technology (CRG/2022/001047). RP acknowledges support from the Indian Council of Medical
Research (AMR/149/2018-ECD-II), Govt. of India. AS thanks support from ICMR (No.52/08/2019BIO/BMS), DST-PURSE program (SR/PURSE Phase 2/29(C)), UP Higher Education (No.
10/2021/281/-4-Sattar-2021-04(2)/2021), and the University of Lucknow. NB thanks for support
from ICMR No. 56/2/Hae/BMS and UGC start-up grant No. 30-496/2019. KA acknowledges the
fellowship support received from ICMR-JRF (Ref. No 3/1/3/JRF2021/HRD(LS)). SAU acknowledges the fellowship support received from UGC-JRF (NTA Ref. No. 22161023985).
Contributions MG, SAU, and AS conceptualized the manuscript. MG, SAU, KA, SC1, SC2, NB,
and AS wrote the manuscript. RP and AS edited, reviewed, and nalized the manuscript.
Financial and Competing Interest Disclosure The authors have no other relevant afliations or
nancial involvement with any organization or entity with a nancial interest in or nancial conict with the subject matter or materials discussed in the manuscript apart from those disclosed.
314
M. Gupta et al.
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M. Gupta et al.
Candidiasis, Drug Resistance,
andTranslational Research
AnubhutiJha andAwanishKumar
Abstract
Candida albicans is a yeast occurring naturally in the human body and causes a
disease candidiasis in immunocompromised person. This pathogen has ideal living and breeding conditions in a healthy person and assembled in susceptible due
to an optimum habitat. This cycle of infection must be understood in order to
understand how infections of C. albicans might arise in human. The understanding and interruption of occurrence of the disease would be helpful to prevent and
control candidiasis. This chapter of the book helps to understand these factors. It
discusses the introductory details of C. albicans and candidiasis, facts of its
pathogenicity mechanisms like white-opaque cellular switching, lamentation,
formation of biolm, and antifungal resistance. Information on translation
research has been also provided.
13
Keywords
Candida albicans · Virulence · Candidiasis · Drug resistance · Translational
research
A. Jha
Department of Biotechnology, St. Thomas College-Bhilai, Hemchand Yadav University,
Durg, CG, India
A. Kumar (*)
Department of Biotechnology, National Institute of Technology, Raipur, CG, India
© The Author(s), under exclusive license to Springer Nature Singapore Pte
Ltd. 2024
S. Hameed, P. Vijayaraghavan (eds.), Recent Advances in Human Fungal
Diseases, https://doi.org/10.1007/978-981-97-4909-6_13
319
320
A. Jha and A. Kumar
13.1 Introduction
Infectious diseases have caused dramatic shifts in demographic, social, economic,
and health indicators over the years, with signicant implications for human life
conditions. Recent medical developments created a false sense of security among
the public, contributing signicantly to the emergence or reemergence of infectious
diseases (Brown etal. 2012). Although it was anticipated that advances in medical
technology would reduce infectious diseases, the exact reverse occurred as people
started to act as vulnerable hosts for more powerful infectious agents. Fungal kingdom has approximately six lac species out of around nine million eukaryotic species
recorded to date, accounting for 8% of all eukaryotic species (Gräser etal. 2018).
Based on cellular characteristics, fungi are more similar and related to humans than
bacteria, and they belong to the Eumycota group of chemoheterotrophic species.
Just 600 species of fungi, on the other hand, are capable of infecting humans. Fungal
infections that are medically signicant are divided into two categories: supercial
infections and invasive mycoses. Mucosal candidiasis and dermatophyte infections
are examples of supercial infections, while invasive infections affect internal body
organs like the connective tissue, central nervous system, kidney, lungs, and liver
(Seneviratne and Rosa 2016). Invasive fungal infections (IFIs) are the leading cause
of the rising incidence and evolving epidemiology of IFIs in this patient population,
posing a signicant diagnostic and therapeutic challenge. The most common causes
of nosocomial IFIs are Candidia albicans, Cryptococcus neoformans, and
Aspergillus fumigatus. Infections with rare/emerging pathogens, such as non-
albicans Candida species, opportunistic yeast-like fungi (e.g., Trichosporon and
Rhodotorula spp.), non-fumigatus Aspergillus., Zygomycetes, and hyaline moulds,
are becoming more common (e.g., Fusarium spp. and Scedosporium spp.) (de
Pauw 2011).
Globally, the rise of fungal infections has resulted in signicant morbidity and
mortality. Even when patients undergo antifungal treatment, mortality among
patients with invasive candidiasis has been conrmed to be as high as 40%
(Chakrabarti etal. 2008).The observed epidemiology is due to fungal pathogens’
developed virulence factors, as well as their high potential for developing antifungal
resistance. The rates vary by geographic area and patient community, but they are
on the rise all over the world. Larger death rates (~70%) combined with rising antifungal resistance raise signicant economic and medical issues (Arendrup et al.
2013). This is linked to an increase in the populace of immunocompromised people,
such as transplant recipients, AIDS patients, and chemotherapy recipients. Longterm use of common antibiotics like penicillin, advanced age, and early biracial
development are also risk factors (Bhattacharjee 2016).
Management and control of infectious diseases triggered by antimicrobial-
resistant pathogens is one of the major challenges faced by modern medicine. A
good understanding of the various factors that inuence the outbreak and severity of
resistance will be needed to meet this challenge (Cleveland etal. 2015). Signicant
determinants of the resistance include the size of the microbial population exposed
13 Candidiasis, Drug Resistance, andTranslational Research
321
to a drug, its mutation rates, and the effect of resistance mechanisms on microbial
tness (Anderson 2005).
Fungi, like all living beings, are classied and recognized by their physical
shapes, molecular structures, and behavioral characteristics. Yeasts are fungal species that exist primarily as single cells, whereas moulds are fungi that are built on
hyphal threads (i.e., hyphal fungi). Hyphae and yeast are microscopic cell types
almost always. A mycelium is a set of hyphal threads, hyphal branches, and any
related spore-bearing structure (Gräser etal. 2006).
Fungal kingdom consists of spectacular collection of decomposers, symbionts,
pathogens, and parasites. They are known to cause extensive damage and losses in
cultivated plants and forestry, e.g., rice blast (Magnaporthe oryzae), chestnut blight
(Cryphonectria parasitica), and other plant pathogens in the genera Fusarium,
Ustilago, Alternariam, and Cochliobolus (Liao etal. 2003). In addition, immuno
compromised people are particularly susceptible to disease by genera such as
Aspergillus, Candida, Cryptococcus, Histoplasma, and Pneumocystis (Chi etal.
2011). Other fungi, known as dermatophytic and keratinophilic fungi, can attack
eyes, nails, hair, and particularly skin, causing local infections like ringworm and
athlete’s foot. Allergies can be triggered by fungal spores, and fungi from various
taxonomic classes can cause allergic reactions (Morse and Schluederberg 1990).
13.2 Candida andCandidiasis
Dermatomycosis is a fungal infection that affects the skin, while disseminated
mycosis is a fungus that affects at least two deep organs as well as the skin. Some
infectious agents must alter their cell shape to enable invasion: these dimorphic
pathogens change from a mould type in their natural environment to a budding,
round-celled form in tissue (Gow et al. 2017). Candidiasis is a fungal infection
caused by Candidia albicans, a species of the genus Candida. Genus Candida is
widespread fungi that are among the most common human fungal pathogens. The
rising prevalence of mucosal and systemic candidiasis is due to an immense increase
in the number of patients at risk, as well as the increased ability for Candida species
to invade tissues that are usually immune to invasion (Kennedy and Sobel 2010).
Candida pathogens are true fungi that take advantage of both external and internal
environment in order to gain access to the circulatory system and deep tissues.
Candida is a genus of around 150 members, but many are endosymbionts of humans
that cause infections primarily in immunocompromised hosts. Candidia albicans
causes about 80% of infections, while Candida -based non-albicans infections
(C. glabrata, C. tropicalis, C. krusei, and C. dubliniensis) are becoming more common (Spampinato and Leonardi 2013).
Increased prevalence of Candida spp. (albicans and non-albicans) has resulted
in new clinical syndromes due to its robust nature and is directly inuenced by status of host immune system (Cheng etal. 2012). Candidemia has been on the rise in
recent years, and it is now the fourth most common cause of bloodstream infections
in hospitals in the United States and the leading cause of nosocomial infection in