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404
S. K. Shishodia et al.
2004a). As reported by Arendrup etal., azole medication treatment has seen a recent
failure in Danish clinical samples against A. terreus and emergence of azole resistance in A. terreus was recently observed with compromised immunity (Arendrup
etal. 2012; Arendrup 2014; Zoran etal. 2018; Pastor and Guarro 2014). According
to a study conducted by Alcazar-Fuoli, Laura et al., A. niger exhibited minimal
variation in MICs in response to ITC (Alcazar-Fuoli etal. 2009; Szigeti etal. 2012)
Moreover, the occurrence of biolm formation in A. niger has been reported (Paul
etal. 2017a; Villena etal. 2009).
Aspergillus avus is predominantly found in dry regions and exhibits a remarkable ability to withstand harsh environmental conditions and known for aatoxin
production and contaminating the food crops causing aatoxicosis, liver necrosis,
and liver cancer (Krishnan etal. 2009; Tiwari and Shankar 2018a). The incidence of
A. avus in India is about 45.4%, and around 2.5% are resistant to VRC with specic genetic abnormalities in the cyp51C gene, namely, T788G and Y319H mutations (Chowdhary etal. 2015; Sharma etal. 2018; Liu etal. 2012b; Paul etal. 2015;
Balajee et al. 2007). The MIC values, however, varied among different azoles
(Rivero-Menendez etal. 2016) due to misuse or prolonged utilization of azole medicines (Hagiwara etal. 2016) or extensive use of fungicides in agricultural practices
(Chowdhary etal. 2013; Snelders etal. 2009; Berger etal. 2017). Moreover, it is
alarming that a signicant number of antifungal drugs nd difcult to control fungal
infections (Van der Linden etal. 2015).
17.1.2 Current Therapeutic Strategies Against
Invasive Aspergillosis
Current therapeutic strategies for IA, a severe fungal infection caused primarily by
Aspergillus species, typically involve antifungal therapies. Voriconazole has been
considered the rst-line treatment for many years, as it has shown efcacy in clinical trials and real-world settings. Other options include AmB formulations, isavuconazole, and posaconazole, especially in cases of intolerance or resistance to
voriconazole. The choice of therapy depends on factors, such as the patient’s underlying health, the severity of the infection, and the susceptibility of the Aspergillus
strain. Combinatorial therapy may also be considered in certain refractory cases.
Timely diagnosis and appropriate management are crucial, as IA can be lifethreatening, particularly in immunocompromised individuals. The current treatment
regime includes azoles, polyenes, and echinocandins group among the antifungal
drugs (Miceli and Kauffman 2015). Echinocandins, such as anidulafungin, caspofungin (CAS), and micafungin, are a class of antifungal medications. The three
mentioned conventional drugs exhibited distinct mechanisms of action when targeting fungal pathogens. In addition to these, AmB tends to bind to ergosterol, resulting in alterations to membrane activities (Arendrup 2014). AmB has demonstrated
diminished efcacy in treating infections caused by A. terreus, particularly those
associated with IA. Furthermore, this reduced effectiveness extends to other
Aspergillus species that have developed resistance to AmB.Combination therapy is
17 Drug-Resistance Patterns in Opportunistic Aspergilli: A Molecular…
405
benecial in circumstances where intrinsic AmB resistance and high toxicityassociated concerns are present (Dannaoui etal. 2004; Elefanti etal. 2013). Toxicity
in humans associated with AmB encompasses several negative effects, particularly
in children aficted with IA.Notably, the administration of AmB at doses ranging
from 3mg/kg to 5mg/kg has been linked to the occurrence of infusion-related illnesses, nephrotoxicity, and hypokalemia (Canadian Paediatric Society ID, UD ICA
2010). Nevertheless, studies have demonstrated that liposomal AmB (L-AMB) can
effectively mitigate toxicity in individuals with IA and exhibit prolonged efcacy
against Aspergillus strains that are resistant to azole medications (Seyedmousavi
etal. 2013). Another class of antifungals known as triazoles is widely recognized
and extensively studied in clinical research. Azole compounds have been found to
have an impact on the production of ergosterol, leading to the disruption of fungal
cell walls’ structure as well as function (Sanglard and Odds 2002). Presently, there
is a global occurrence of resistance to azoles in A. fumigatus, which poses a concern
to azole therapy for aspergillosis (Verweij etal. 2016). The Aspergillosis Medication
Guidelines advise using voriconazole (VRC) for IA.ITC and POS may be used for
salvage therapy in addition to VRC. As voriconazole is the preferred treatment,
azole-resistant strains have increased, resulting in more clinical failures. Thus, azole
(VRC) and echinocandins are used to treat both azole-resistant and azole- susceptible
A. fumigatus isolates. Echinocandin inhibits cell wall biosynthesis by preventing
β-glucan biosynthesis (Arendrup 2014). In the context of combination therapy, it
was observed that COS and VRC demonstrated efcacy against invasive pulmonary
aspergillosis (IPA) caused by A. niger and A. avus; however, limitations have been
reported in IPA caused by A. fumigatus (Krishnan-Natesan etal. 2012; Zhang etal.
2014). Noteworthy, a combination of regimen showed a decrease in mortality rate
(19.3%) as compared to the use of monotherapy (27.5%) (Marr etal. 2015). In addition, a strategies need to be extend for improved therapy to successfully address the
current situation (Denning etal. 2013).
Globally, signicant concerns arise from medication toxicity and the elevated
exposure of humans to fungicides (Damalas and Eleftherohorinos 2011; Dorner
2004). Further investigation into new therapeutic targets for fungal infections is
required due to the structural resemblances shared by fungal cells and human cells
(Scorzoni etal. 2017). In addition, a signicant proportion of pathogenic fungi have
developed a mechanism of resistance to commonly used antifungal medications
employing the processing, over-expression, and proliferation of fungal biolm proteins (da Silva Ferreira etal. 2004; Mowat etal. 2009). The calcineurin signaling in
Aspergilli is associated with the protein of calcineurin and its involvement in various biological processes (Juvvadi etal. 2017). In addition, it plays a role in the regulation of ergosterol biosynthesis, chitin production, and β-glucan synthesis.
Furthermore, there has been a recent discovery of triphenylethylene as a novel
chemical that effectively inhibits the calcineurin pathway through the activation of
calmodulin (Cramer etal. 2008; Jacob etal. 2015; Shankar etal. 2018b). Therole
of calcineurin–Crz1 signaling under antifungal has been studied in Aspergillus a-
vus (Shishodia etal. 2020). Moreover, the targeting of microtubule synthesis inhibi-
tion and heat shock proteins (Hsp90 and Hsp70) has been identied as novel
406
strategies for antifungal treatment (Jacob etal. 2015). Furthermore, less toxic antifungals such as N-methyl-N--fructose have been developed in the last decade
through the use of innovative antimicrobial formulations and structural enhancements. One such AmB derivative is AmB methyl ester (Szlinder-Richert etal. 2001).
Echinocandins are presently the prevailing antifungal pharmaceutical drugs that
have obtained licensing. This particular family of antifungal drug inhibits the formation of cell wall components during fungal infections (Pianalto and Alspaugh
2016). Furthermore, novel azole compounds (PC945 and PC1244) were synthesised
to specically target and combat aspergillosis and counteract resistance in strains of
A. fumigatus (Colley etal. 2017). In addition, olorom (F901318) is a newly discov-
ered drug that has shown promise in combating life-threatening Aspergillus infec-
tions (Buil etal. 2017). Therefore, it is imperative to consider alternate therapeutic
approaches, such as immunotherapy utilizing antifungal agents (Thakur and
Shankar 2017a).
In conclusion, the efcacy, accessibility, and adverse effects of existing antifungal medications are relatively insignicant. The prolonged utilization and improper
administration of these medications have been found to result in the emergence of
drug-resistant strains (Denning and Bromley 2015). Recent studies indicate that the
emergence of drug-resistant fungal strains has elevated invasive fungal infections to
become the most signicant global threat (Chowdhary etal. 2017; Lockhart etal.
2017; Navalkele etal. 2017). Currently, no FDA-approved vaccines are effective.
The frequent exposure to environmental fungi, commensally related to other fungi
and fragile immune responses in immunocompromised patients, makes effectiveness of the vaccine attempt difcult (McCarthy etal. 2017). Some vaccines have
shown promise in clinical trials, but many obstacles remain (Sandini etal. 2011).
Thus, immune mechanisms must be understood to develop an anti-fungal vaccine.
S. K. Shishodia et al.
17.2 The Molecular Dissection oftheResistance Mechanism
inAspergilli
The efcacy of antifungal medications employed in the management of diverse
manifestations of aspergillosis is hindered by the emergence of resistance in
Aspergillus. Moreover, the protracted utilization of antifungal medication constitutes a signicant factor contributing to the development of acquired drug resistance. The outcome is contingent upon various factors, including the specic
Aspergillus species, the efcacy of antifungal medications, and the geographical
context. While there are available data on drug-resistance genes and mutations in
the genome, the restricted range of therapeutic options poses challenges in effectively managing invasive secondary fungal infections. The primary classications of
drug-resistance mechanisms encompass three major categories. First, alterations in
drug targets occur as a result of mutations in the target, leading to a reduced binding
capacity between the drug and its target. Second, drug efcacy is diminished due to
various factors, such as increased drug efux, overexpression of drug targets, and
sequestration of antifungal drugs. Finally, metabolic bypass includes the
17 Drug-Resistance Patterns in Opportunistic Aspergilli: A Molecular…
407
establishment of compensatory mechanisms that negate the antifungal agents
(Sanglard 2016).
The investigation of Aspergilli genome sequencing facilitatesthe knowledge on
the pathogenesis and the metabolic pathways of mycotoxins (Thakur and Shankar
2017b), including drug resistance. The investigation of Aspergilli mRNA has the
potential to elucidate the organism’s ability to react to outer stimuli, such as antifungal drugs or morphological switch (Shankar etal. 2018a). In addition, they facilitate
the prediction of interactions between host pathogens in both in-vitro and in-vivo
scenarios (Thakur and Shankar 2019). However, it is important to note that mRNAlevel studies alone may not offer a comprehensive understanding without the inclusion of functional investigations, such as proteomics analysis (Shankar 2022;
Shishodia and Shankar 2020). Mellado etal. (2001) reported that the primary targets of azoles are the Cyp51A and Cyp51B proteins. These two entities are encoded
by distinct genes, although they exhibit a sequence identity of 63%. Azole-resistant
strains of A. fumigatus exhibit resistance mechanisms through the presence of point
mutations or overexpression of the cyp51A gene (Mellado et al. 2001;Snelders
etal. 2010). Triazoles exhibit an interaction with the active site of Cyp51A, hence
impeding the process of ergosterol production. Fungal cell death is attributed to
changes in membrane uidity, as documented by (Snelders et al. 2009) and
(Chowdhary etal. 2014). The extensive utilization of several azole fungicides in
agricultural settings has demonstrated a comparable molecular composition to
medicinal triazoles, leading to the emergence of cross-resistance in clinical applications (Snelders etal. 2012). In a recent study conducted by Hagiwara etal. 2016, an
examination was carried out on the mutation occurrences at various locations within
the cyp51 genes, as well as the tandem repeats in the promoter region (TR34/L98H
and TR46/Y121F/T289A) in Aspergilli (Hagiwara etal. 2016). The major molecular determinants contributing for Azole resistance in Aspergillus is tabulated in
Table17.1.
Previous studies have proposed that the overexpression of genes in A. terreus
involved in the manufacture of ergosterol, including ERG5, ERG6, and ERG25,
may provide resistance to AmB (Barker etal. 2004; Deak etal. 2009; Walsh etal.
2003). According to Blum etal. (2013), it has been observed that Aspergillus strains
exhibit reduced absorption of the AmB medication. In addition, resistance isolates
of A. terreus have demonstrated more effective protective mechanisms against oxi-
dative damage caused by the drug (Blum etal. 2013). Based on a recent study by
Jukic etal. (2017), it was observed that in Aspergilli, strains with AmB resistance
exhibited higher superoxide dismutase (SOD) activity as compared to susceptible
isolates. SOD functions to mitigate the harmful effects of superoxide anions, which
serve as the precursors for reactive oxygen species (ROS) (Jukic et al. 2017).
Furthermore, Bruns etal. (2010a) discovered a signicant increase in the production
of gliotoxin, a redox-active metabolite, in the biolms of A. fumigatus. This elevate
the production of gliotoxin contributes to the resistance of A. fumigatus by facilitating its growth and persistence within the host tissue (Bruns etal. 2010a).
Blatzer etal. (2015a) propose that Hsp70, a crucial protein, may serve as a regulator for AmB resistance. The utilization of inhibitors targeting Hsp70 and Hsp90
408
References
Snelders etal. (2012),
Snelders etal. (2010),
common
Amino acid
substitution Remark
Howard and Arendrup
(2011), Losada etal.
(2015) and Vahedi
Shahandashti and
Lass-Flörl (2019)
mechanism
Barker etal. (2004),
Howard and Arendrup
(2011) and Losada etal.
(2015)
susceptibilities
E, K, R, V, W No azole
Losada etal. (2015),
Vahedi Shahandashti and
Lass-Flörl (2019) and
Howard and Arendrup
(2011)
Losada etal. (2015) and
Vahedi Shahandashti and
susceptibility to
voriconazole
K, I, T, V Variable
posaconazole
S. K. Shishodia et al.
Lass-Flörl (2019)
Losada etal. (2015),
Vahedi Shahandashti and
Lass-Flörl (2019) and
Howard and Arendrup
susceptibilities not
reported
combination with
TR34/L98H
(2011)
Azole resistant
phenotype
Pan-azole H Highly resistant
Function
Cytochrome P-450-dependent enzyme
Gene encoding drug-
resistance determinant
Table 17.1 Molecular determinants and cellular alterations that confer azole resistance against Aspergillus spp. (Szalewski etal. 2018)
cyp51A a.k.a. erg11A
Itraconazole,
posaconazole
involved in sterol biosynthesis
(14-sterol demethylase)
(Afu4g06890)
Ergosterol biosynthesis in Aspergillus
involves C-22 sterol desaturase (erg5),
erg5 (Afu1g03950), erg6
(Afu4g03630), erg25
Itraconazole and
Posaconazole
resistant
(24)-sterol C-methyltransferase (erg6),
and C-4 methyl sterol oxidase (erg25),
with uconazole resistance being a
potential issue
methylglutaryl coenzyme A reductase,
a crucial enzyme in mevalonate
(Afu8g02440) (orthologs
to ERG5, ERG6, and
ERG25 in C. albicans)
hmg1 (Afu2g03700) Mutations in 3-Hydroxy-3-
Itraconazole D Voriconazole and
synthesis and ergosterol biosynthesis,
are linked to voriconazole resistance
ssc70 (Afu2g09960) Putative mitochondrial Hsp70
Pan-azole H Reported in
chaperone; a high level of resistance to
itraconazole
signaling; multiple azole resistance
ganA (Afu3g12400) G-protein involved in cAMP-mediated
17 Drug-Resistance Patterns in Opportunistic Aspergilli: A Molecular…
References
Losada etal. (2015),
Vahedi Shahandashti and
Lass-Flörl (2019) and
Howard and Arendrup
(2011)
Kanafani and Perfect
combination with
Amino acid
substitution Remark
G448
1 Balashov etal. (2006) and
during
(2008)
long-term
Samar etal. (2015)
azole
treatment
I Reported only in
Lamoth etal. (2014) and
Howard and Arendrup
combination with
TR34/L98H
posaconazole
A Voriconazole and
(2011)
Al Abdallah etal. (2012),
Vahedi Shahandashti and
susceptibilities not
reported
voriconazole and
S Susceptibility to
Lass-Flörl (2019) and
Howard and Arendrup
(2011)
Abdallah and Fortwendel
Posaconazole
T Reported only in
409
(continued)
(2015) and Vahedi
Shahandashti and
Lass-Flörl (2019)
combination with
TR34/L98H
Azole resistant
phenotype
Pan-azole Y Reported in
Function
ABC multiple drug transporter;
multiple azole resistance
Gene encoding drug-
resistance determinant
ABC transporter
(Afu4g14760)
Pan-azole, G, K Acquired
fks1 (Afu6g12400) 1,3--Glucan synthetase activity and
Itraconazole and
posaconazole
resistant
the likely lethal target of
echinocandins; SNPs are associated
with resistance
proposed mixed-linkage glucosyl
transferase, which is hypothesized to
tft1 (Afu3g03620) Current evidence suggests that the
Itraconazole
resistant
be involved in the mechanisms of
action of caspofungin, is not accurate
and cell wall integrity; enzyme
Hsp90 (Afu5g04170) Heat-shock chaperone for conidiation
itraconazole
overproduction determines resistance
to caspofungin
Ras family GTPase proteins Pan-azole,
rasA (Afu5g11230), rasB
(Afu2g07770)
Itraconazole,
pan-azole and
posaconazole
resistant
farnesyltransferase activity
ram1 (Afu4g10330) Ortholog(s) have protein
410
References
Abdallah and Fortwendel
(2015) and Vahedi
and posaconazole
Amino acid
substitution Remark
Shahandashti and
Lass-Flörl (2019)
Howard and Arendrup
(2011) and Panepinto
etal. (2002)
Pais etal. (2016)
susceptibilities
found
susceptibilities
S. K. Shishodia et al.
susceptibilities
Azole resistant
phenotype
Itraconazole L No Voriconazole
Function
Gene encoding drug-
resistance determinant
Table 17.1 (continued)
erfD (Afu3g06470) Zinc ion binding activity; potential
palmitoyl transferase activity
rhbA (Afu5g05480) Ras-related signaling protein Itraconazole K, T, V No azole
Ergosterol No azole
Upc2B was shown to regulate the
expression of Erg2 and Erg3
Upc2
Transcriptional factor
17 Drug-Resistance Patterns in Opportunistic Aspergilli: A Molecular…
411
has been found to substantially enhance the effectiveness of AmB and azole medicines in resistant A. terreus isolates (Blatzer etal. 2015a, b; Cowen and Lindquist
2005; Tiwari etal. 2015). Antimicrobial resistance toward Aspergillus includes itra-
conazole, azoles, echinocandin, voriconazole, uconazole, ketoconazole, and
AmB. Aspergillus species causes aspergillosis, cutaneous aspergillosis, aspergilloma, and paranasal sinuses, whose therapeutic options are decreasing due to
increasing drug resistance (Howard and Arendrup 2011). Multiazole and pan-azole
resistance is the most common type. The transcriptional factor responsible for mediating azole drug resistance in Aspergillus is SrbA.SrbA is a member of SREBP
family which conceals bHLH proteins. Drug resistance is mediated by switching on
the inference of cyp51 and the ERG11 orthologs in the pathogen. SrbA shares
sequential similarities with SrbB. These two regulators upon coming together
upregulate the heme biosynthesis and sterol demethylation genes (Pais etal. 2016).
We have endeavored to gather all relevant data and establish connections between
molecular factors and cellular alterations that contribute to the development of antifungal resistance in the most prevalent species of Aspergillus. This information is
presented in Fig.17.1.
17.2.1 Role ofBiofilm inDrug Resistance
Microscopic organisms grow on sediment, skin, bark, rock, and mucosal tissues
(Desai etal. 2014; Kolter and Greenberg 2006). The majority of bacterial and fungal
pathogens in humans form biolms, which hinder drug response and host immunity.
Biolm matrix may protect fungal cells from antifungals. Biolm formation by
A. terreus is less studied than other species. A. fumigatus forms biolms with
parallel- packed hyphae (Seidler etal. 2008) and an ECM (Al Abdallah etal. 2012).
To eliminate biolm structures, A. fumigatus needs a higher MIC of antifungal drug,
which is why it is drug-resistant. Biolm’s extracellular matrix may absorb antifungal molecules and prevent them from reaching fungal cells, conferring drug resistance. C. albicans ECM locks up antifungal drugs and reduces drug susceptibility
(Nett et al. 2010). Antifungal drug-releasing multidrug-resistance protein is activated in biolms. Current research links biolm development and drug resistance to
cell wall protein cspA (Fan etal. 2015). Researchers have found biolms on dialysis
catheters, including α-1, 3-glucans, Galactomannan, melanins, proteins, and hyphal
cells (Loussert etal. 2010; Rajendran etal. 2013; Ramage etal. 2011). Along with
this evidence, transcription factors have been studied for their role in biolm formation. Agglutinin-like sequence (ALS) proteins and Hyr1-like CFEM proteins indicate their involvement. An efux-pump role in azole resistance has been
well-documented, which may contribute to aspergillosis treatment failure (Rajendran
et al. 2013). At biolm formation, metabolic changes linked to virulence are
observed (Muszkieta etal. 2013). Until now, the potential has been observed that in
A. fumigatus, ECM releases eDNA and glycosaminoglycans, which aid drug resistance. Drug resistance in biolm is also caused by increased MDR transporter production and overexpression of genes involved in iron metabolism, ergosterol
412
S. K. Shishodia et al.
Fig. 17.1 Key molecular modulators of drug resistance against Aspergillus spp. Current medications possess inherent and acquired resistance mechanisms,
which encompass mutations in any of the crucial genes in Aspergillus spp. result in (c) modications in the target protein/enzyme, which subsequently cause
(a) changes in the binding sites and lead to target incompatibility. The (b), outow of drugs is enhanced by transmembrane transport proteins known as ABC
transporters, which are regulated by AtrR, a transcription factor that controls ABC transporter activity. In addition, (d) impairing ergosterol biosynthesis through
deletion or dysfunction leads to disruption of cell wall components. Remodeling of the cell wall results in the formation of biolms and the switching of meta-
bolic processes, which are regulated by Hsp90/Hsp70. Furthermore, (e) these alterations in metabolic pathways result in oxidative stress within the mitochon-
dria, which can be counteracted by the antioxidant enzymes Catalase and SOD.The explanation of all routes leads to the modication of the TCA cycle, ETC,
glycolysis, cell wall components, and signaling pathways, which contribute to antifungal tolerance in Aspergillus. Overall, the Cellular resistance mechanisms
are intricately connected to molecular alterations in Aspergillus species. Note: ECM extracellular matrix, GAG galactosaminogalactan, NADH dehydrogenase,
Nicotinamide adenine dinucleotide dehydrogenase, ROS reactive oxygen species, CRZ1 calcineurin-regulated zinc nger transcription factor, HSP heat shock
protein, FKs1 1,3-beta-glucan synthase, CYP51 sterol 14 alpha demethylase, ERG11 lanosterol 14 alpha demethylase, ERG5 C-22 sterol desaturase, ERG6
C24-sterol C-methyltransferase, ERG25 C-4 methyl sterol oxidase, SrbB signal recognition particle B (a small GTPase protein), PtaB protein tyrosine phos-
phatase B, AtrR ABC transcriptional factor
17 Drug-Resistance Patterns in Opportunistic Aspergilli: A Molecular…
413
pathways, ABC, and MFS transporters. Hypoxic microenvironment and nutritional
gradients cause metabolic adaptation, including downregulation of TCA cycle, glycolysis induction, and amino acid metabolism changes, as shown in Fig.17.1 (Liu
etal. 2022). Unfortunately, current treatments are failing to treat these dangerous
biolm-related infections, so more research is needed to determine how biolms
affect drug resistance. Rayón-López etal. 2023 investigated brain biolm formation
in A. terreus and found nucleic acid, carbohydrates, proteins, and lipids. They iden-
tied A. terreus isolates with lipid-like biolms that may increase AmB resistance
(Rayón-López etal. 2023). In an AmB-resistant isolate of A. terreus, Sonia etal.
noted the role of few secretory protein-induced biolm formation. These secretory
proteins may play a crucial role in understanding the role of biolms in drug resistance (Sonia Kumari and Jata 2020). Thus, by understanding the lipids metabolism
lamentous fungi biolms, more research is needed.
17.2.2 Combating Drug Resistance inAspergilli
It is imperative to comprehend the metabolic modications in drug-resistant isolates
and susceptible isolates of Aspergilli. The emergence of drug resistance is facilitated by a range of mechanisms, such as the alteration of drug–target interactions
via the upregulation or downregulation of proteins implicated in cell wall modulation, oxidative stress, heat shock proteins, and energy metabolism. In addition, antifungal resistance is inuenced by various factors, including redox imbalance,
homeostasis of ROS, and changes in membrane uidity in aspergilli. An alternative
mechanism contributing to antifungal drug resistance involves the creation of biolms, facilitating the attachment of fungal cells to the surface of the host. The primary molecular targets of azole antifungal agents are the enzymes Cyp51A and
Cyp51B.The proteins Hsp70 and Hsp90 play a signicant role in cellular protection
under conditions of stress. As per literature, Sod2, Cat1, thioredoxin peroxide,
Hsp70, and Hsp90 as potential targets in Aspergillus isolates exhibit resistance
(Shishodia et al. 2019). We attempt to collect all information and correlate all
molecular factors to cellular changes that contribute to antifungal-resistance mechanism against most leading species of Aspergillus, as presented in Fig.17.1.
Thus, understanding various metabolic and immunological pathways is crucial
to develop vaccine against Aspergillus infection or drugs to tackle the drug resistance. In this context, our laboratory is also focusing on the investigation of new
drug targets in aspergilli. The literature-based analysis revealed that 72 Aspergillus
proteins are abundant during interaction with antifungal agents and 26 proteins are
affected by multiple antifungal molecules that showed general stress response
(Shishodia etal. 2019; Shishodia and Shankar 2020). The crucial role of proteins
such as Sod2, Prx1/LsfA, thioredoxin peroxide (Aspf 3), enolase, Cat1, Hsp70, and
Hsp90 was found in Aspergilli under the inuence of antifungal, further exploring
that the role of these proteins in the resistant mechanism may provide detailed
insight into the drug-resistance mechanism (Shishodia et al. 2019). Figure 17.2
demonstrates the critical signicance of all these molecular determinants in the