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7 Factors Aecting Drug Resistance andVirulence inFungal Pathogen
Ramage G, Saville SP, Wickes BL, López-Ribot JL (2002b) Inhibition of Candida albicans bio-
lm formation by farnesol, a quorum-sensing molecule. Appl Environ Microbiol 68:5459.
https://doi.org/10.1128/AEM.68.11.5459- 5463.2002
Ramage G, Mowat E, Jones B, Williams C, Lopez-Ribot J (2009) Our current understanding of
fungal biolms. Crit Rev Microbiol 35:340–355. https://doi.org/10.3109/10408410903241436
Ramanan N, Wang Y (2000) A high-afnity iron permease essential for Candida albicans viru-
lence. Science 288:1062–1064. https://doi.org/10.1126/science.288.5468.1062
Rasheed M, Battu A, Kaur R (2018) Aspartyl proteases in Candida glabrata are required for
suppression of the host innate immune response. J Biol Chem 293:6410–6433. https://doi.
org/10.1074/jbc.M117.813741
Rocha MC, Minari K, Fabri JHTM, Kerkaert JD, Gava LM, da Cunha AF, Cramer RA, Borges
JC, Malavazi I (2021) Aspergillus fumigatus Hsp90 interacts with the main components of the
cell wall integrity pathway and cooperates in heat shock and cell wall stress adaptation. Cell
Microbiol 23:e13273. https://doi.org/10.1111/cmi.13273
Samanovic MI, Ding C, Thiele DJ, Darwin KH (2012) Copper in microbial pathogenesis: meddling
with the metal. Cell Host Microbe 11:106–115. https://doi.org/10.1016/j.chom.2012.01.009
Sanglard D, Ischer F, Monod M, Bille J (1997) Cloning of Candida albicans genes conferring resis-
tance to azole antifungal agents: characterization of CDR2, a new multidrug ABC transporter
gene. Microbiology (Reading) 143(Pt 2):405–416. https://doi.org/10.1099/00221287- 143-
2- 405
Sanglard D, Ischer F, Parkinson T, Falconer D, Bille J (2003) Candida albicans mutations in the
ergosterol biosynthetic pathway and resistance to several antifungal agents. Antimicrob Agents
Chemother 47:2404–2412. https://doi.org/10.1128/aac.47.8.2404- 2412.2003
Santos R, Costa C, Mil-Homens D, Romão D, de Carvalho CCCR, Pais P, Mira NP, Fialho AM,
Teixeira MC (2017) The multidrug resistance transporters CgTpo1_1 and CgTpo1_2 play a role
in virulence and biolm formation in the human pathogen Candida glabrata. Cell Microbiol
19:e12686. https://doi.org/10.1111/cmi.12686
Sardari A, Zarrinfar H, Mohammadi R (2019) Detection of ERG11 point mutations in Iranian
uconazole- resistant Candida albicans isolates. Curr Med Mycol 5:7–14. https://doi.
org/10.18502/cmm.5.1.531
Shah AH, Singh A, Dhamgaye S, Chauhan N, Vandeputte P, Suneetha KJ, Kaur R, Mukherjee PK,
Chandra J, Ghannoum MA, Sanglard D, Goswami SK, Prasad R (2014) Novel role of a family
of major facilitator transporters in biolm development and virulence of Candida albicans.
Biochem J 460:223–235. https://doi.org/10.1042/BJ20140010
Shapiro RS, Uppuluri P, Zaas AK, Collins C, Senn H, Perfect JR, Heitman J, Cowen LE (2009)
Hsp90 orchestrates temperature-dependent Candida albicans morphogenesis via Ras1-PKA
signaling. Curr Biol 19:621–629. https://doi.org/10.1016/j.cub.2009.03.017
Silva S, Henriques M, Martins A, Oliveira R, Williams D, Azeredo J (2009) Biolms of non-
Candida albicans Candida species: quantication, structure and matrix composition. Med
Mycol 47:681–689. https://doi.org/10.3109/13693780802549594
Singh RP, Prasad HK, Sinha I, Agarwal N, Natarajan K (2011) Cap2-HAP complex is a critical
transcriptional regulator that has dual but contrasting roles in regulation of iron homeostasis in
Candida albicans. J Biol Chem 286:25154–25170. https://doi.org/10.1074/jbc.M111.233569
Singh DK, Németh T, Papp A, Tóth R, Lukácsi S, Heidingsfeld O, Dostal J, Vágvölgyi C, Bajtay Z,
Józsi M, Gácser A (2019) Functional characterization of secreted aspartyl proteases in Candida
parapsilosis. mSphere 4. https://doi.org/10.1128/msphere.00484- 19
Slaven JW, Anderson MJ, Sanglard D, Dixon GK, Bille J, Roberts IS, Denning DW (2002)
Increased expression of a novel Aspergillus fumigatus ABC transporter gene, atrF, in the pres-
ence of itraconazole in an itraconazole resistant clinical isolate. Fungal Genet Biol 36:199–206.
https://doi.org/10.1016/s1087- 1845(02)00016- 6
Smith DFQ, Mudrak NJ, Zamith-Miranda D, Honorato L, Nimrichter L, Chrissian C, Smith B,
Gerfen G, Stark RE, Nosanchuk JD, Casadevall A (2022) Melanization of Candida auris is
associated with alteration of extracellular pH.J Fungi (Basel) 8:1068. https://doi.org/10.3390/
jof8101068
199
200
Song J, Li R, Jiang J (2019) Copper homeostasis in Aspergillus fumigatus: opportunities for thera-
peutic development. Front Microbiol 10:774
Spacek J, Jilek P, Buchta V, Főrstl M, Hronek M, Holeckova M (2005) The serum levels of
calcium, magnesium, iron and zinc in patients with recurrent vulvovaginal Candidosis
during attack, remission and in healthy controls. Mycoses 48:391–395. https://doi.
org/10.1111/j.1439- 0507.2005.01164.x
Steinbach WJ, Cramer RA, Perfect BZ, Asfaw YG, Sauer TC, Najvar LK, Kirkpatrick WR,
Patterson TF, Benjamin DK, Heitman J, Perfect JR (2006) Calcineurin controls growth, mor-
phology, and pathogenicity in Aspergillus fumigatus. Eukaryot Cell 5:1091–1103. https://doi.
org/10.1128/EC.00139- 06
Sudbery PE (2011) Growth of Candida albicans hyphae. Nat Rev Microbiol 9:737–748. https://
doi.org/10.1038/nrmicro2636
Theiss S, Ishdorj G, Brenot A, Kretschmar M, Lan C-Y, Nichterlein T, Hacker J, Nigam S, Agabian
N, Köhler G (2006) Inactivation of the phospholipase B gene PLB5in wild-type Candida
albicans reduces cell-associated phospholipase A2 activity and attenuates virulence. Int J Med
Microbiol: IJMM 296:405–420. https://doi.org/10.1016/j.ijmm.2006.03.003
Tian X, Ding H, Ke W, Wang L (2021) Quorum sensing in fungal species. Ann Rev Microbiol
75:449–469. https://doi.org/10.1146/annurev- micro- 060321- 045510
Tisi R, Rigamonti M, Groppi S, Belotti F, Tisi R, Rigamonti M, Groppi S, Belotti F (2016) Calcium
homeostasis and signaling in fungi and their relevance for pathogenicity of yeasts and lamen-
tous fungi. AIMSMOLES 3:505–549. https://doi.org/10.3934/molsci.2016.4.505
Tsitsigiannis DI, Kowieski TM, Zarnowski R, Keller NP (2005) Three putative oxylipin biosyn-
thetic genes integrate sexual and asexual development in Aspergillus nidulans. Microbiology
151:1809–1821. https://doi.org/10.1099/mic.0.27880- 0
Ueno K, Namiki Y, Mitani H, Yamaguchi M, Chibana H (2011) Differential cell wall remodeling
of two chitin synthase deletants Δchs3A and Δchs3B in the pathogenic yeast Candida gla-
brata. FEMS Yeast Res 11:398–407. https://doi.org/10.1111/j.1567- 1364.2011.00728.x
Uppuluri P, Nett J, Heitman J, Andes D (2008) Synergistic effect of calcineurin inhibitors and
uconazole against Candida albicans biolms. Antimicrob Agents Chemother 52:1127–1132.
https://doi.org/10.1128/AAC.01397- 07
Valand N, Brunt E, Gazioglu O, Yesilkaya H, Mitchell D, Horley N, Arroo R, Kishore U, Wallis
R, Venkatraman Girija U (2022) Inactivation of the complement lectin pathway by Candida
tropicalis secreted aspartyl protease-1. Immunobiology 227:152263. https://doi.org/10.1016/j.
imbio.2022.152263
Vila T, Sultan AS, Montelongo-Jauregui D, Jabra-Rizk MA (2020) Oral candidiasis: a disease of
opportunity. J Fungi (Basel) 6:15. https://doi.org/10.3390/jof6010015
Vu BG, Simonicova L, Moye-Rowley WS (2023) Calcineurin is required for Candida glabrata
Pdr1 transcriptional activation. MBio 14(6):e02416-23. https://doi.org/10.1128/mbio.02416- 23
Walton FJ, Idnurm A, Heitman J (2005) Novel gene functions required for melanization of the
human pathogen Cryptococcus neoformans. Mol Microbiol 57:1381–1396. https://doi.
org/10.1111/j.1365- 2958.2005.04779.x
Warrilow AGS, Martel CM, Parker JE, Melo N, Lamb DC, Nes WD, Kelly DE, Kelly SL (2010)
Azole binding properties of Candida albicans sterol 14-α demethylase (CaCYP51). Antimicrob
Agents Chemother 54:4235–4245. https://doi.org/10.1128/AAC.00587- 10
Wasi M, Khandelwal NK, Moorhouse AJ, Nair R, Vishwakarma P, Bravo Ruiz G, Ross ZK, Lorenz
A, Rudramurthy SM, Chakrabarti A, Lynn AM, Mondal AK, Gow NAR, Prasad R (2019) ABC
transporter genes show upregulated expression in drug-resistant clinical isolates of Candida
auris: a genome-wide characterization of ATP-binding cassette (ABC) transporter genes. Front
Microbiol 10:1445. https://doi.org/10.3389/fmicb.2019.01445
Widiasih Widiyanto T, Chen X, Iwatani S, Chibana H, Kajiwara S (2019) Role of major facili-
tator superfamily transporter Qdr2p in biolm formation by Candida glabrata. Mycoses
62:1154–1163. https://doi.org/10.1111/myc.13005
Wilkens S (2015) Structure and mechanism of ABC transporters. F1000Prime Rep 7. https://doi.
org/10.12703/P7- 14
P. Sharma et al.
7 Factors Aecting Drug Resistance andVirulence inFungal Pathogen
Yamaguchi-Iwai Y, Serpe M, Haile D, Yang W, Kosman DJ, Klausner RD, Dancis A (1997)
Homeostatic regulation of copper uptake in yeast via direct binding of MAC1 protein to
upstream regulatory sequences of FRE1 and CTR1. J Biol Chem 272:17711–17718. https://
doi.org/10.1074/jbc.272.28.17711
Yu J-H (2010) Regulation of development in Aspergillus nidulans and Aspergillus fumigatus.
Mycobiology 38:229–237. https://doi.org/10.4489/MYCO.2010.38.4.229
Zaragoza O (2019) Basic principles of the virulence of Cryptococcus. Virulence 10:490–501.
https://doi.org/10.1080/21505594.2019.1614383
Zaragoza O, Rodrigues ML, De Jesus M, Frases S, Dadachova E, Casadevall A (2009) The capsule
of the fungal pathogen Cryptococcus neoformans. Adv Appl Microbiol 68:133–216. https://
doi.org/10.1016/S0065- 2164(09)01204- 0
Zaugg C, Borg-Von Zepelin M, Reichard U, Sanglard D, Monod M (2001) Secreted aspartic
proteinase family of Candida tropicalis. Infect Immun 69:405–412. https://doi.org/10.1128/
IAI.69.1.405- 412.2001
Zhang Y, Muend S, Rao R (2012) Dysregulation of ion homeostasis by antifungal agents. Front
Microbiol 3:133
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Unravelling Drug Resistance inCandida
Species: Genetic, Biofilm,
Transcriptional, andEpigenetic
Perspectives
AjeetKumar, AshikFrancis, SandeepHans, andAnilThakur
Abstract
Candida species infections pose a substantial threat in the realm of human-
induced fungal diseases, particularly impacting immunocompromised individu-
als. While various Candida species contribute to systemic candidiasis, the
existing antifungal arsenal remains limited, and resistance is on the rise. However,
the emergence of drug resistance, particularly in non-albican species, poses a
grave threat to current therapeutic approaches. This phenomenon involves pri-
mary, acquired, and clinical resistance, inuenced by various factors like host
immunity, pharmacokinetics, and fungal pathobiology. Genetic alterations play a
central role, affecting key genes encoding enzymes vital for antifungal
susceptibility.
Biolms present a signicant challenge to antifungal treatments, acting as a
shield and hindering drug impact. The complex biolm structure, including lamentous hyphae, pseudo-hyphae, blastospores, persister cells, and extracellular
matrix components, collectively contributes to Candida’s resilience and survival.
Efux transporters, mainly ABC and MFS groups, actively expel intracellular
drugs, playing a crucial role in drug resistance. The comprehensive understanding of genetic variations, biolm dynamics, transcriptional regulation, and epigenetic modications collectively contributes to drug resistance, impacting
antifungal efcacy and patient outcomes. This chapter discusses the multifaceted
nature of Candida drug resistance, covering genetic alterations, drug efux
pumps, biolm intricacies, transcriptional regulations, and epigenetic modications. Addressing these complexities requires innovative solutions and therapeutic targets, exploring synergies, and enhancing treatment outcomes. The
8
A. Kumar · A. Francis · S. Hans · A. Thakur (*)
Laboratory of Protein Translation and Fungal Pathogenesis, Regional Centre for
Biotechnology, Faridabad, Haryana, India
e-mail: anil.thakur@rcb.res.in
© 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_8
203
204
A. Kumar etal.
unravelling Candida drug resistance mechanisms holds promise for developing
precise interventions and improving antifungal strategies to combat these challenging infections effectively.
Keywords
Candida · Biolm · MDR · ABC · MFS
8.1 Introduction
Candida species are the most common fungal pathogens in humans, causing diverse
infections, including candidiasis (thrush), vulvovaginal candidiasis, and invasive
candidiasis. Antifungal drugs are the mainstay of treatment for Candida infections,
but the emergence of drug resistance poses a signicant threat, especially in nonalbican species those are shown to develop resistance to virtually all the classes of
antifungal drugs available, including azoles, echinocandins, and polyenes (Cowen
etal. 2014; Jacobs et al. 2022). Analogous to the antibiotic resistance in bacteria,
antifungal resistance in Candida species is a complex phenomenon and can be primary/intrinsic, where the resistance occurs without the exposure to antifungals,
acquired—when the exposure to antifungal therapy leads to genetic or epigenetic
changes ultimately resulting in resistance, and clinical resistance—as a result of
failure of antifungal therapy and depends upon multiple factors like host immune
system, pharmacokinetic nature of the antifungal used, and pathobiology of the
infecting fungus (McCarthy etal. 2017).
Genetic alterations are central to the development of drug resistance in Candida
species. Mutations in key genes, such as those encoding lanosterol 14α-demethylase
for azoles, β-1,3-glucan synthase for echinocandins, and ergosterol for polyenes,
can impact the susceptibility of Candida to antifungal agents. The intricate network
of resistance mechanisms also includes the expression and overexpression of drug
efux pumps encoded by the Candida drug resistance (CDR) genes, which are vital
in expelling drugs and ultimately contribute to the emergence of drug resistance. In
addition to this, biolm formation further complicates multidrug resistance in
Candida species. Biolm formation, a protective strategy employed by fungus, creates cohesive microbial communities that adhere to surfaces, complicating the eradication of infections and fostering resistance. Furthermore, biolms serve as a
breeding ground for chronic and recurring infections, making their eradication a
challenging task. Additionally, environmental factors such as temperature, pH, and
nutrient availability further inuence the susceptibility of Candida species to antifungal agents. Transcription factors hold a pivotal position in fungal pathogens,
directing responses to antifungal resistance. Their role involves the regulation of
gene expression in various key pathways such as drug efux pumps, cell wall integrity, and stress response. These pathways are essential for the pathogen’s survival in
8 Unravelling Drug Resistance in Candida Species: Genetic, Biolm…
Fig. 8.1 An overview into the combined regulatory factors inuencing drug-resistant phenotype
in Candida species
205
the presence of antifungal agents. Through the modulation of gene expression, transcription factors shape the overall resistance prole of fungal pathogens.
Furthermore, these factors may also govern the activation of stress response pathways, contributing to an increased tolerance of the fungus to antifungal agents. The
recent elucidation of epigenetic alterations has shed light on their role in drug resistance. Epigenetic modications refer to changes in gene expression that do not
entail alterations in the underlying DNA sequence (Patra etal. 2022). Typically,
these modications are mediated through post-translational modications (PTMs),
or RNA interference (RNAi) mechanisms. While reports on RNAi-based epigenetic
inheritance in Candida species are currently limited, numerous studies have implicated PTMs in the development of epigenetic modications associated with antifungal resistance.
The dynamic and multifaceted nature of drug resistance in Candida species
necessitates a comprehensive understanding of the underlying mechanisms. Genetic
variations, alterations in gene expression, biolm formation, transcriptional factor,
and environmental factors regulating the epigenetic modications collectively contribute to the development of resistance (Fig.8.1), impacting the efcacy and efciency of antifungal drugs and, subsequently, leading to higher mortality rates
caused by Candida infections. Here we will elucidate the following:
206
• Role of genetic alteration and contribution of lipid homeostasis in drug resistance in Candida species.
• Overexpression of drug efux pumps observed in fungal pathogens, making
them more resistant to antifungal treatments (Gong etal. 2023).
• Different components of biolm and mechanism through the formation of biolms act as a shielding barrier against the effects of antifungals, thereby increasing the resilience of Candida species (Deng etal. 2021).
• Mutations in different transcription factors reduce the susceptibility of Candida
species to antifungals (Momin and Webb 2021; Avramovska and Hickman 2019;
Ene etal. 2018).
• The involvement of epigenetic modications in contributing to drug resistance in
Candida species through their inuence on changes in gene expression in
response to various environmental factors, without necessitating alterations in
the underlying DNA sequence.
In conclusion, tackling Candida infections requires understanding the dynamic
resistance mechanisms. Ongoing research shows potential in discovering new therapeutic targets, enabling precise interventions, and improving antifungal strategies.
Exploring synergies, like combining antifungal drugs with immune-modulating
agents or disrupting drug-sensing signals, offers opportunities for enhanced treatment outcomes. Diligent efforts to unravel the complexities of Candida drug resistance will yield insights guiding the development of innovative solutions to address
this healthcare challenge.
A. Kumar etal.
8.2 Genetic Alterations andDrug Resistance
inCandida Species
Genetic alterations play a pivotal role in the development of drug resistance in
Candida species, inuencing various genes and their functions based on particular
antifungal drugs (as illustrated in Fig.8.2). Different genes may undergo genetic
changes causing resistance to antifungal drugs, depending on the specic class of
drug available to treat fungus. The resistance to azole drugs in Candida spp. is often
caused by mutations in the ERG11 gene, which encodes for the lanosterol
14α-demethylase enzyme, crucial for ergosterol biosynthesis, a key component of
the fungal cell membrane (Cheng etal. 2006).
Azole drugs exert their therapeutic effect by inhibiting the action of Erg11, lead-
ing to a reduction in ergosterol levels and eventually causes the death of the fungal
cell. However, mutations in the ERG11 gene can weaken the binding ability of azole
drugs to the enzyme, resulting in resistance to azole treatment by the fungus
(Gomez-Gaviria etal. 2023). Extensive research has been conducted on azole resistance in Candida albicans and other emerging non-albicans Candida species. The
current understanding of the molecular mechanisms underlying this resistance has
been highly documented and described, shedding light on the intricate interplay of
genetic alterations in the context of antifungal drug responses.
8 Unravelling Drug Resistance in Candida Species: Genetic, Biolm…
207
Fig. 8.2 Illustration of different mechanisms of drug resistance in Candida species due to altera-
tions in its genetic material, leading to phenotypic changes that promote adaptation to the antifungal drugs. These changes include: (1) overexpression of efux pumps, namely, CDR1, CDR2,
MDR1, etc.; (2) genetic changes which lead to alteration of various drug targets like alerted FKS1,
ergosterol, etc., which reduces the binding of the respective drug to the target molecule (ERG3);
(3) overexpression of drug targets due to mutations resulting in the duplication of the target gene
(ERG11); (4) changes in membrane and cell wall composition due to the incorporation of unusual
molecules or changes in the ratio of various lipids in the cell membrane composition
Azoles function as antifungal agents by inhibiting lanosterol 14α-demethylase
(Erg11p) and this inhibition leads to the accumulation of toxic sterol intermediates
and a depletion of ergosterol in the fungal membrane. They include uconazole, itraconazole, voriconazole, posaconazole, and isavuconazole. They have a variable spectrum of activity against different Candida species, depending on their afnity for
Erg11p and their ability to penetrate fungal cells (Paul etal. 2022). They have fewer
side effects than polyenes, but they can interact with other drugs metabolized by cytochrome P450 enzymes (Godamudunage etal. 2018). Resistance to azoles is common
in Candida species, especially in C. glabrata and C. auris. Resistance to azole can
occur due to several mechanisms, such as mutations or overexpression of ERG11
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A. Kumar etal.
gene, which reduce the binding of azoles to Erg11p; overexpression or activation of
efux pumps, such as Cdr1p, Cdr2p, or Mdr1p, which decrease the intracellular concentration of azoles; or alterations in membrane composition or permeability, which
affect azole uptake or retention (Carolus etal. 2021). Various studies have shown that
Y132F, K143R, and F126L substitution in the ERG11 gene confers azole resistance
in both C. auris and C. albicans (Lockhart 2019; Lockhart etal. 2017). Particularly in
C. albicans, overexpression of ERG11 is frequently observed in azole-resistant clinical strains, which leads to target abundance thereby reducing the effect of the azolebased drugs (Revie etal. 2018). A gain of function mutation UPC2, a transcriptional
activator for the ERG11, enables C. albicans to constitutively express genes involved
in ergosterol biosynthesis, and it has been shown that the disruption of UPC2 in azoleresistant clinical isolates has indeed increased azole-susceptibility in those isolates
(Flowers etal. 2012; Dunkel etal. 2008a). A similar mechanism has also been reported
in C. glabrata (Whaley etal. 2014).
The echinocandin drugs work by inhibiting Fks1, which encodes the β-1,3-
glucan synthase enzyme. This enzyme is essential for the synthesis of β-1,3-glucan,
a major component of the fungal cell wall (Perlin 2007). Inhibition of Fks1 by echinocandin leads to weakening of the fungal cell wall and eventual inhibition of fungal growth. Resistance to echinocandin drugs is mostly caused by mutations in the
hot-spot (HS) region of FKS genes. Due to the presence of a natural polymorphism
in the FKS1 gene (P660A) in Candid aparapsilosis, echinocandin resistance mechanism in C. parapsilosis differs from the phenotypic changes seen in the presence
of echinocandin, compared to other Candida species, suggesting that the mechanisms employed by the organism to develop resistance against these drugs may vary
at a species level (Pristov and Ghannoum 2019). Thus far, a single mutation, F652S,
has been pinpointed exclusively in the HS1 of FKS1 within a clinical isolate of panechinocandin- resistant C. parapsilosis. This mutation has not been observed in any
susceptible isolates. Additionally, the R658G mutation is specically associated
with micafungin mono-resistant isolates, and a heterozygous mutation, F1386S,
located outside of the HS, has been identied in a clinical isolate resistant to
anidulafungin.
Echinocandins encompass caspofungin, micafungin, and anidulafungin, exhibit-
ing a broad spectrum of activity against most Candida species, with exceptions
being C. parapsilosis and C. guilliermondii. Echnocandins have low toxicity and
few drug interactions (Perlin 2007; Lee etal. 2021). Resistance to echinocandins is
emerging in Candida species, especially in C. glabrata and C. albicans. In the case
of C. albicans, serine 645 (S645) in the FKS1 is associated with echinocandins
resistance (Garcia-Effron etal. 2009). Similarly, resistance to echinocandins in the
case of C. glabrata and C. auris has been associated with serine 663in FKS2 and
serine 639in FKS1 respectively (Garcia-Effron etal. 2009; Chowdhary etal. 2018).
Echinocandin resistance can occur due to mutations in FKS genes, overexpression
of FKS genes or other genes involved in cell wall biosynthesis, and remodelling,
such as CHS2, CHS8, CRH11, GSC1, and KRE5, which alter the sensitivity of
Fks1p/Fks2p to echinocandins (Perrine-Walker 2022).
8 Unravelling Drug Resistance in Candida Species: Genetic, Biolm…
209
Polyene drugs on the other hand function by attaching to ergosterol in the fungal
cell membrane, creating pores that disturb cell integrity and ultimately result in cell
death. Resistance to polyenes may arise due to genetic alterations leading todecrease
in ergosterollevel in the cell memberane(Baginski and Czub 2009).
Certain Candida species like C. glabrata and C. auris have intrinsic azole and
uconazole resistance, exhibiting elevated MIC to the respective drugs, and there is
very little that we know about the molecular basis of this mechanism. A recent study
has shown that TAC1b, a zinc cluster transcription factor, is responsible for the u-
conazole resistance in C. auris by increasing the production of efux pumps, allowing the possibility of transcriptional regulation to be the key in explaining the
intrinsic resistance in Candida species (Rybak etal. 2020; Mayr etal. 2020; Perlin
etal. 2017). Efux pumps and mutations in lanosterol 14-alpha-demethylase have
also been suggested as potential mechanisms of antifungal resistance in C. auris for
polyene drugs (de Cassia Orlandi Sardi etal. 2018).
8.2.1 Genetic Mechanism ofAntifungal Resistance
inCandida Species
These polyenes including amphotericin B and nystatin exert their effect by binding
to ergosterol, the main sterol component of fungal membranes, and disrupt membrane integrity and function. They have a broad spectrum of activity against most
Candida species, but their use is hindered by notable serious side effects such as
nephrotoxicity and infusion-related reactions. Resistance to polyenes is rare in
Candida species except in the case of C. lusitaniae (Iguchi etal. 2019). Resistance
can arise due to factors like reduced ergosterol content or altered ergosterol structure in the membrane mostly because of therapeutic or prophylactic exposure. This
can be caused by mutations or overexpression of genes involved in ergosterol biosynthesis, such as ERG1, ERG3, ERG6, ERG11, or ERG25.
Numerous mutations and diverse mechanisms exist across different Candida
species (Table8.1). The resistance to polyenes in Candida encompasses a sophisticated process, implicating several genes. The following are some of the identied
genes involved in this process in the case of the recently identied multidrug resistance fungus C. auris:
(a) ERG11: The ERG11 gene, which is responsible for the production of lanosterol
14α-demethylase, a key enzyme in the ergosterol biosynthesis pathway, can
undergo mutations leading to resistance (Logan etal. 2022). Based on genomic
studies, three separate substitution mutations, F126T, Y132F, and K143F, in the
ERG11 gene have been detected in C. auris and are associated with polyene
resistance (Iguchi etal. 2019; Ostrowsky etal. 2020).
(b) ERG3: Nonsense mutations in the ERG3 gene, which also plays a role in ergos-
terol synthesis, can decrease susceptibility to amphotericin B (Carolus
etal. 2021).