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are also secreted via the adaptive immune response to prevent its overgrowth and
proliferation (Netea etal. 2015).
4.8.2 Biofilm Formation
The formation of biolm is a salient feature of C. albicans for the development and
retention of infection for longer duration on the surface of the host or on abiotic
surfaces (implants), which leads to high morbidity and mortality (Tsui etal. 2016).
The overall architectural stability of the biolm is contributed by a hyphae form
(Fig.4.6), and act as a support scaffold for yeast cells, pseudohyphae, other hyphae,
and other microbial cells in the context of polymicrobial biolms (Chandra etal.
2001; Xu etal. 2014; Gulati and Nobile 2016). Normal biolm development requires
the adherence of hyphae to one another and to cell morphologies. This adherence is
also crucial for the maintenance of biolm (Nobile and Johnson 2015).
A study in 2012 conducted on the large and complex transcriptional network controlling the development of C. albicans biolms was described (Nobile etal. 2012).
This network comprises six “master” transcriptional regulators (Efg1, Tec1, Bcr1,
Ndt80, Brg1, and Rob1), each of them is required for the development of normal
A. Aachment
D. Dispersion
B. Division of cell and
hyphal transion
Fig. 4.6 Life cycle of biolm production by C. albicans. (a) Oval yeast cell adhere to the surface.
(b) Initiation of morphological switching and formation of biolm. (c) Maturation of biolm takes
place by producing complex extracellular matrix. (d) Dispersion of yeast cells to spread to
new surface
C. Producon of
extracellular matrix
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P. Srivastava et al.
biolm. The main culprit for the biolm development is Bcr1 genes. Bcr1 gene is the
master regulator for the adherence of hyphal cells to one another (Nobile and Mitchell
2005). Biolms of C. albicans help in providing protection from host immune attack
as well as it is also responsible for ineffectiveness of antifungal drugs (Andes etal.
2012; Mazu etal. 2016). Biolm is a complex network of yeast, pseudohyphal, and
hyphal cells entangled in the extracellular matrix partly secreted by C. albicans itself.
It may also contain aggregates from lysed C. albicans and host cells. An extracellular
matrix gives a three-dimensional architectural stability of the biolm (Gulati and
Nobile 2016). The matrix is a complex of more than 500 proteins, most of which are
hydrolytic enzymes. This identication of enzymes gives an idea of how an extracellular matrix also plays an active role in protection, source of nutrients, and the digestion of biopolymers (Zarnowski etal. 2014; Gulati and Nobile 2016).
4.8.3 C. albicans Biofilms Subvert theInnate Immune Response
The innate immune response of the host in which biolm of pathogen is recognized
and surrounded by neutrophils fails to trigger the production reactive oxygen species
(ROS) and bursting of cell because of the presence of some antiimmune factors or we
can say virulence factors in the extracellular matrix of biolm which helps in escaping the immune system (Xie etal. 2012). Carbohydrates like glucans are responsible
for the inhibition of neutrophil activation. There are some proteins Pra1, Gpd2, and
members of the secreted aspartyl protease (Sap) family that are capable of blocking
complement activation (Gropp etal. 2009; Gulati and Nobile 2016) and are highly
expressed during biolm formation. Msb2 is another protein involved in recognizing
and inhibiting antimicrobial peptides secreted by host (Gulati and Nobile 2016).
Hyphal cells are another important component of biolms that contribute to subversion of the innate immune response. The hyphal cells of biolm also help to
escape phagosome by piercing physically and forming a pore through their elongated tube and thus escaping the phagocytic cell (Ghosh etal. 2009). When hyphal
cells are phagocytosed by immune cells, Candida secretes many of the protective
enzymes and proteins including superoxide dismutase, catalase, thioredoxin, avohaemoglobin, and glutathione recycling enzymes that degrade or scavenge reactive
nitrogen species (RNS) and ROS (Dantas Ada etal. 2015; Kaloriti etal. 2015).
It also has been reported that Candida hyphal cells share a property with
Cryptococcus and other fungi to be able to induce their own nonlytic expulsion
from macrophages (sometimes called vomocytosis), without any damage to the
phagocyte (Bain etal. 2012).
4.8.4 C. albicans Adaptations totheHost Environment
As C. albicans is a commensal of the human microora, it also shares environment
with other microbiota present in the host. To survive in that competitive environment, fungus has developed a unique mechanism through which it isolates nutrients
4 MDR inCandida: TheReal Storm
99
from neighbouring microbes. The mechanism involves the expression of transporter
protein like Rbt5/Als3 protein for the transport of Fe and Zrt1/Zrt2/ Soluble Pra1 for
the transport of Zn (Crawford and Wilson 2015), redundant enzymes that use alternative micronutrients as cofactors (Li etal. 2015). To absorb nutrients like amino
acids and carbon sources, C. albicans secretes enzymes like secretory aspartates
(Saps). These enzymes can digest host tissue, and by digestion, release of these
nutrients will take place. Unlike many other commensal microbes, C. albicans is
able to utilize several different carbon sources, and is thus able to grow in many
distinct and dynamic environmental regions of the body (Gow and Hube 2012). As
C. albicans lives in various distinct environments like systemic blood stream,
vagina, and GUT, they require some adaptation mechanism to live in those broad pH
spectra. Proteins like Phr1 and Phr2 let C. albicans to adapt the changing pH levels
(Gulati and Nobile 2016).
4.8.4.1 Antifungals
There are loads of antibiotic drugs from numerous antibiotic classes following various modes of action that are available against different bacterial targets. In the case
of fungi, current antifungal drugs are extremely limited in spectrum. Only four
major classes of antifungal drugs are explored to treat most fungal diseases: azoles,
polyenes, echinocandins, and nucleoside analogues.
Azoles (e.g., uconazole, ketoconazole, and itraconazole) are fungistatic, that
means they inhibit the growth of fungus. They are the most prescribed class of antifungals used to treat both systemic and topical infections. Like cholesterol in human
cells, ergosterols are responsible for asymmetry and uidity in the cell membrane of
fungal cells (Quindós etal. 2019), and thus, by targeting ergosterol biosynthesis
intermediates like demethylase Erg11 (Geber etal. 1995), it causes the pathway to
not proceed and leads to accumulation of toxic ergosterol pathway intermediates.
Polyenes (e.g., amphotericin B) are antifungals that can kill the fungal cell and
thus fall in the category of fungicidal antimicrobials. These antifungals are used as
a standard to treat severe fungal infections, as they are the oldest antifungal discovered (Cowan 1999). Polyenes also target the sterols present in the fungus membrane. An aqueous pore is created in the plasma membrane due to the association
between polyenes and sterols, resulting in ion leakage and destabilization of the
fungal cell membrane (De Kruijff and Demel 1974; Holz 1974).
Echinocandins (e.g., caspofungin) are the latest class of antifungals yet discovered, which are fungicidal against most Candida species. Echinocandins inhibit the
synthesis of β-1,3-glucans noncompetitively (Hector 1993), which are unique polysaccharide components and carries functional importance for fungal cell walls. The
inhibition of this polysaccharides causes various drastic changes in cell wall of fungus. The changes are characterized as thickening of the cell wall and failure of
removal of bud from mother cells (Traxler et al. 1977; Cassone etal. 1981). The
inhibition of β-1,3-glucans synthesis also causes the reduction of ergosterol content
and increases in the chitin content of the wall of the fungal cell (Pfaller etal. 1989).
Nucleoside analogues (e.g., 5-uorocytosine (5-FC)) act as an inhibitor of pyrimidine biosynthesis. With the help of a permease enzyme, 5-FC enters inside the cell. By
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P. Srivastava et al.
following several metabolic steps, 5-FC is converted into 5- uorodeoxyuridine monophosphate, which acts on thymidylate synthase enzyme and inhibits it (Polak and
Scholer 1975). Thus, inhibiting synthesis of DNA, RNA, and protein leads to arrest of
the cell cycle (Diasio etal. 1978; Ghannoum and Rice 1999).
According to the World Health Organization, antimicrobial resistance is dened
as when viruses, bacteria, fungi, and parasites modify over time and no longer
respond to available antimicrobials, making treatment harder and increasing the
severity of disease. As a result, antimicrobials become useless and infections start to
become impossible to treat (Murray etal. 2022).
4.8.4.2 Antifungal Resistance
Due to overexploitation and exposure to the antifungal drugs, microbes start adapting
different resistant mechanisms to survive and thrive in their niches. Although the cases
of resistance to antifungals in C. albicans are not very common, resistance has been
reported during the treatment of fungal infections in some cases. Continuous exposure
of antifungals, such as patients suffering from uncontrolled HIV infection, can lead to
development of chronic mucocutaneous candidiasis due to the development of resistance to antifungals (Arendrup and Patterson 2017; Berman and Krysan 2020).
Before understanding the mechanism by which fungus has developed resistance,
we must know what the concept and denition of resistance as well as its different types.
The term resistance can be dened as a strain that has a minimal inhibitory concentration (MIC) greater than a reference or a control strain (Lee etal. 2021). In a
joint initiative by the European Centre for Disease Prevention and Control and the
US Centres for Disease Control and Prevention (CDC), denitions for multidrugresistant (MDR), extensively drug-resistant (XDR), and pan drug-resistant (PDR)
bacteria were established (Arendrup and Patterson 2017). According to them, MDR
as the name itself explains an organism which has acquired resistance to at least one
drug in three or more antimicrobial classes.
XDR an organism which has developed resistance to every available antimicrobial agent except 1 or 2 classes.
PDR was dened as an organism which has acquired resistance to all available
antimicrobial classes. However, for candida these denitions do not directly adopted
due to availabilty of four classes of antifungals.
In patients suffering with AIDS and oropharyngeal or mucosal candidiasis, the
development of resistance to the currently prescribed azole group of antifungals has
become a major concern (Revankar etal. 1996; Marr et al. 1998; Arendrup and
Patterson 2017).
4.8.5 Molecular Mechanism Adapted by Fungi
asAntifungal Resistance
During evolution, fungi have also developed various modes of resistance mechanism
(Fig.4.7), so that it can remain in the race of survival in nature. The various mechanisms
which are responsible for the development of resistance to antifungals are as follows.
4 MDR inCandida: TheReal Storm
Drug
101
Target
Overproducon of
Fig. 4.7 Molecular mechanisms of antifungal drug resistance. Resistance for azole group of antifungals mediates by altering target, overexpressing efux pumps as well as overproducing the
target whereas for polyenes and echinocandins, C. albicans only follows alteration of their targets
Alteraon of target
Resistance for Polyenes,
azole, echinocandins
target
Resistance for
Azoles
Over expression of
efflux pump
Resistance for
Azoles
4.8.5.1 Alterations inDrug Targets
By modifying the target of drugs, most of the microbes develop resistance. It is the
most found resistance method adapted by any microbe. By changing the target site
of drugs, microbes hide the target, so that drugs can never bind with them and can
never initiate their method of action.
Azoles As we have learned earlier, the target of the azole group of antibiotics is the
intermediate of ergosterol biosynthesis pathway, that is demethylase enzyme
ERG11. Thus, the mechanism adapted by C. albicans is to alter the demethylase
enzyme by substituting amino acid sequence. This substitution causes decrease in
binding afnity of drug with ERG11 (Lamb etal. 1997; Revie etal. 2018). It has
been discovered that substitution of approximately 140 amino acids are associated
with an azole group of resistance, and the amino acid substitution sequences are
present in clusters like from 105 to 165, 266 to 287, and 405 to 488 amino acid
(Marichal etal. 1999).
Polyenes In case of C. albicans, resistance to polyenes is very less common. This
rare kind of resistance can be found in other species like C. lusitaniae, C. glabrata,
and C. guilliermondii (Martins and Rex 1996). As we have studied earlier, the target
molecule for polyene antifungal is ergosterol; hence, the mechanism for resistance
to polyenes is to reduce ergosterol content in the membrane. This mechanism is one
of its own kind because by decreasing the ergosterol content, binding afnity with
polyenes will also get reduced (Dick etal. 1980). The decrease is not due to any
enzymatic degradation of the already produced ergosterol instead the rate of
ergosterol biosynthesis is reduced (Capek etal. 1974). In C. albicans, the enzymes
which are mutated in this kind of resistance mechanisms include ERG2,62,
ERG3,63, ERG5,64, and ERG11 (Sanglard etal. 2003).
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P. Srivastava et al.
Echinocandins The target site for this lipopeptide antifungal is a heterodimeric
glucan synthase enzyme which is encoded by some FKS genes (Kurtz and Douglas
1997). As echinocandins are not clinically used antifungals, the resistance mecha-
nisms adapted by fungal cells for echinocandins are discovered by laboratory methods and laboratory derived mutants (Kurtz and Douglas 1997). By mutating and
substituting amino acid sequence in these FKS genes at specic hotspot regions,
resistance is being developed by most of Candida species. In C. albicans, mutation
in the FKS1 gene at several hotspot regions like from amino acids 641–649 (hotspot
1) and amino acids 1357–1364 (hotspot 2) cause the lipopeptide ineffective (Park
etal. 2005b; Perlin 2007; Garcia-Effron etal. 2009a, b).
Nucleoside Analogues The target enzyme for 5-FC is thymidilate synthase enzyme
involved in DNA and RNA synthesis, and the inhibitor is uorodeoxyuridine monophosphate produced from the conversion of 5-FC (Diasio etal. 1978). The resistance mechanism adapted by C. albicans for these analogues is by blocking the
enzymes involved in the conversion of 5-FC to FUMP. Cytosine deaminase and
uracil phosphoribosyl transferase (UPRTase) are not required by fungus for the
pyrimidine synthesis in normal conditions, where a de novo pathway is an alternative available; hence, loss of these enzymes can be afforded by the fungal cells
(Polak and Scholer 1975; Iwata 1992).
4.8.5.2 Overexpression ofEfflux Pump
The upregulation and overexpression efux pumps present in the plasma membrane
of the fungal cell are major mechanisms responsible for the ineffectiveness of
antifungals.
Azole The efux pump present in azole resistant strains belongs to ATP binding
cassette (ABC) superfamily and major facilitator superfamily (MFS) (Jenkinson
1996). The genes responsible for the production of the ABC efux pump are CDR1
and CDR2 (Revie etal. 2018; Robbins etal. 2017). The structure consists of four
core domains, in which two domains are integral membrane domain which makes
the passage for transport and two cytoplasmic domain which bind ATP to promote
the transport of drug by ATP hydrolysis. A study shows that if the resistant strain
CDR1 gene is deleted, then the resistance property is also reduced by four- to eightfold for the azoles class (Tsao etal. 2009). Another study experimentally proves the
expulsion of azole derivatives like uconazole, Itraconazole, etc. by transporter protein CDR1 protein (Sanglard etal. 1995). The structure of MFS also carries membrane spanning helix, and they use the proton gradient for the transport or expulsion
of drugs. The MFS class of the efux pump includes a protein named as BENr
which, involves only the expulsion of uconazole specically (Coleman and
Mylonakis 2009).
Polyenes and Echinocandins Due to the complex large structure and functions of
the echinocandins, the overexpression of efux pumps does not show any signicance in developing resistance. The target of echinocandins is present in the out
4 MDR inCandida: TheReal Storm
103
leaet of the cell membrane; hence, the overexpression of efux pump will be
meaningless. Likewise, polyenes are unable to enter in the pockets of transporters
where drugs can bind; hence for them, the overexpression of the efux pump does
not help in conferring resistance (Cannon etal. 2009).
4.8.5.3 Overexpression ofDrug Target
This kind of resistance mechanism is common for the azole group of antimicrobials,
in which the target molecules are produced in abundance, so that the biochemical
pathway cannot be completely inhibited by drug.
Azoles As the target of the azole class of drug is ERG11, the C. albicans overpro-
duces this enzyme leading to reduction in susceptibility for the drug (Revie etal.
2018; Robbins etal. 2017). The master enzyme involved in the ergosterol biosyn-
thesis pathway is UPC2. To confer this kind of resistance, C. albicans has been
evolved in a way that introduces a gain of function mutation in UPC2 gene, which
lead to hyperactivation of the ergosterol synthesizing genes and overproduction of
ergosterol which ultimately leads to the reduction in susceptibility azole groups of
antifungals (Hoot etal. 2011).
4.9 Conclusion andFuture Perspective
Due to the lack of diverse antifungals and drug resistance, it has become tough to
handle invasive infection caused by fungi. This resulted in high morbidity and mortality. The emergence of different levels of drug resistance in Candida made the
situation very difcult. MDR reported in Candida pose an alarming situation. At
present, different researchers strike to nd out novel antifungals. Until that, we must
follow right antifungals, right dose, and right duration.
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