Candida auris is a multidrug-resistant species associated with high morbidity and mortality in immunocompromised individuals worldwide.
- Candida auris
- resistance
- antifungal
- biofilm
- infection
- novel therapy
1. Candida auris
and Treatment Failure of Common Commercial Antifungal Drugs
C andida auris is a multidrug-resistant species associated with high morbidity and mortality in immunocompromised individuals worldwide [12]. As mentioned, the key characteristics of
is a multidrug-resistant species associated with high morbidity and mortality in immunocompromised individuals worldwide [1]. As mentioned, the key characteristics of
C. auris comprise spreading easily in the environment, transiting quickly among hospitalization patients [62,63], as well as being resilient to common disinfectants in the healthcare setting [64]. The lack of availability of microbiological diagnostic methods and subsequent misidentification [65,66] and high levels of antifungal resistance [36,67] makes
comprise spreading easily in the environment, transiting quickly among hospitalization patients [2][3], as well as being resilient to common disinfectants in the healthcare setting [4]. The lack of availability of microbiological diagnostic methods and subsequent misidentification [5][6] and high levels of antifungal resistance [7][8] makes
C. auris
as a potential virulent species, and globally emerging pathogen, causing challenges to control policies against infection.
The number of antifungal drugs targeting the treatment of
C. auris infection have been limited. Generally, three main classes of available antifungal including azoles, polyenes, and echinocandins have been used for treatment of infected patients in the clinics [27]. Different countries have reported various levels of resistance to common antifungals used against
infection have been limited. Generally, three main classes of available antifungal including azoles, polyenes, and echinocandins have been used for treatment of infected patients in the clinics [9]. Different countries have reported various levels of resistance to common antifungals used against
C. auris infections worldwide, as described by Sekyere [68]. In this study, a systematic review and meta-analysis were carried out on 267
infections worldwide, as described by Sekyere [10]. In this study, a systematic review and meta-analysis were carried out on 267
C. auris clinical isolates in 16 countries in 2019, and the analysis of data displayed that resistance to Flu, AmB, voriconazole (Vcz), and caspofungin was 44.29%, 15.46%, 12.67%, and 3.48%, respectively. Two novel drugs, SCY-078 and VT-1598, are currently in the pipeline [68].
clinical isolates in 16 countries in 2019, and the analysis of data displayed that resistance to Flu, AmB, voriconazole (Vcz), and caspofungin was 44.29%, 15.46%, 12.67%, and 3.48%, respectively. Two novel drugs, SCY-078 and VT-1598, are currently in the pipeline [10].
In contrast, the first case report in China investigated that the
C. auris
isolated from bronchoalveolar lavage fluid (BALF) of a hospitalized woman interestingly was sensitive to Flu, AmB, and echinocandins. Additionally, the copper sulfate (CuSO4) also had a potent antifungal effect on
C. auris [69]. Likewise,
[11]. Likewise,
C. auris isolate as a causative agent of urinary tract infection (UTI) showed sensitivity to AmB and echinocandins, and in the case of refractory and persistence of infections and different combination therapy, flucytosine are recommended as an appropriate alternatives therapy [70].
isolate as a causative agent of urinary tract infection (UTI) showed sensitivity to AmB and echinocandins, and in the case of refractory and persistence of infections and different combination therapy, flucytosine are recommended as an appropriate alternatives therapy [12].
C. auris isolates of patients with candidemia in Russia were susceptible to echinocandins, whereas the high-level of resistance against Flu and AmB was seen in the majority of isolates. More investigation regarding surveillance might be helpful to achieve proper guidelines for the management of candidemia [71].
isolates of patients with candidemia in Russia were susceptible to echinocandins, whereas the high-level of resistance against Flu and AmB was seen in the majority of isolates. More investigation regarding surveillance might be helpful to achieve proper guidelines for the management of candidemia [13].
Response to antifungal agents have also indicated a significant difference between the planktonic and sessile state of
C. auris
growth.
C. auris enable biofilm structures to form on both medical implementation surfaces in immunocompromised patients and bio-surfaces [50,72] that are strongly associated with the type and phenotypic behavior of the isolates [73]. Additionally, biofilms are capable of triggering the antifungal resistance in this species and developing the persistent infection [74]. Romea et al. found that the minimum biofilm eradication concentration (MBEC) was higher than the minimum inhibitory concentration (MIC) against antifungal drugs. In addition, biofilm was resistant to all classes of antifungals drugs; whereas, it was sensitive to echinocandins and polyenes. Therefore, the biofilm feature seems a fundamental factor to antifungal resistance in
enable biofilm structures to form on both medical implementation surfaces in immunocompromised patients and bio-surfaces [14][15] that are strongly associated with the type and phenotypic behavior of the isolates [16]. Additionally, biofilms are capable of triggering the antifungal resistance in this species and developing the persistent infection [17]. Romea et al. found that the minimum biofilm eradication concentration (MBEC) was higher than the minimum inhibitory concentration (MIC) against antifungal drugs. In addition, biofilm was resistant to all classes of antifungals drugs; whereas, it was sensitive to echinocandins and polyenes. Therefore, the biofilm feature seems a fundamental factor to antifungal resistance in
C. auris [75]. It has been reported that
[18]. It has been reported that
C. auris
clinical isolates with a mutation in
FKS1
gene were echinocandin resistant, whereas
FKS1
wild-type (WT) isolates were sensitive. The findings suggested micafungin represented the most potent echinocandin against
C. auris. In addition, all WT isolates showed the Eagle effect (paradoxical growth effect) against the caspofungin susceptibility test performed according to the CLSI microdilution method [76]. However, echinocandins are only available intravenously and are related to increasingly higher rates of resistance by
. In addition, all WT isolates showed the Eagle effect (paradoxical growth effect) against the caspofungin susceptibility test performed according to the CLSI microdilution method [19]. However, echinocandins are only available intravenously and are related to increasingly higher rates of resistance by
C. auris.
Thus, a need exists for novel treatments that reveal potent activity against
C. auris
. Recently, therapies focused on echinocandins’ synergism with other antifungal drugs were widely explored, representing a novel possibility for the treatment of
C. auris infections [77].
infections [20].
2. Facing the Challenges to Fight against
Candida auris
: Molecular Resistance Mechanisms
The majority of clinical
C. auris isolates display resistance to main classes of antifungals (azoles, polyenes, or echinocandins), and there is multi (MDR)- or pan-drug resistance to more than two antifungal classes [13]. Many research groups have studied the molecular mechanisms implicated in resistance development, resulting in limited therapeutic options [13,78]. As previously noted, in order to not fail in treatment of
isolates display resistance to main classes of antifungals (azoles, polyenes, or echinocandins), and there is multi (MDR)- or pan-drug resistance to more than two antifungal classes [21]. Many research groups have studied the molecular mechanisms implicated in resistance development, resulting in limited therapeutic options [21][22]. As previously noted, in order to not fail in treatment of
C. auris infections, accurate detection and identification of this pathogen is necessary [35,78]. Setting the MICs of antifungals against
infections, accurate detection and identification of this pathogen is necessary [23][22]. Setting the MICs of antifungals against
C. auris strains has also been requested, since elevated MICs are severe problem [79]. Importantly, it is equally critical to monitor the antifungal resistance in different geographical areas and implement efficient guidelines for treatment [45].
strains has also been requested, since elevated MICs are severe problem [24]. Importantly, it is equally critical to monitor the antifungal resistance in different geographical areas and implement efficient guidelines for treatment [25].
The antifungal resistance in
C. auris has been shown to be acquired rather than intrinsic [80]. Currently, the worldwide findings conclude that susceptibility to Flu is the most decreased from
has been shown to be acquired rather than intrinsic [26]. Currently, the worldwide findings conclude that susceptibility to Flu is the most decreased from
C. auris isolates, followed by AmB, and 5-fluorocytosine and echinocandins are also not 100% effective [36,81]. WGS studies revealed that
isolates, followed by AmB, and 5-fluorocytosine and echinocandins are also not 100% effective [7][27]. WGS studies revealed that
ERG3
,
ERG11
,
FKS1
,
FKS2
, and
FKS3
homologs were found in the
C. auris
genome and these loci share around 80% similarity with
C. albicans
and
C. glabrata genes [79,82,83]. In general, preliminary genomic studies showed that the targets of several classes of antifungal drugs are conserved in
genes [24][28][29]. In general, preliminary genomic studies showed that the targets of several classes of antifungal drugs are conserved in
C. auris
, including the azole target lanosterol 14-α-demethylase (
ERG11
), the echinocandin target 1,3-β-(D)-glucan synthase (
FKS1
), and the flucytosine target uracil phosphoribosyl-transferase (
2.1. Mechanisms of Resistance to Azoles
Mechanistically, resistance to azole is acquired through different mechanisms; a number of genes encoding efflux pumps, including ATP-binding cassette (ABC) and overexpressed major facilitator superfamily (MFS) transporters are well known for deliberate major multidrug resistance in
genome contains three genes encoding Mrr1 homologs and two genes encoding Tac1 homologs. Mutations in the zinc cluster transcription factors Mrr1 and Tac1 cause intrinsic Flu resistance of
[32]. Deletion of
decreased the resistance to Flu and Vcz in both mutant Flu-resistant strains from clade III and clade IV. It has been shown that the encoded transcription factor is associated with azole resistance in
strains from different clades [32].
expression was not or only minimally affected in the mutants, representing that
can confer increased azole resistance by a
-independent mechanism. A recent study from Rybak et al. suggested that the Δcdr1 mutation in a resistant isolate was able to increase susceptibility to Flu and itraconazole by 64- and 128-fold, respectively, with notable reductions in MIC also demonstrated in other azoles [33][34]. The function of efflux pumps in azole resistance appears to be predominantly associated with
, as analysis of the Δmdr1 mutant showed minimal effects on increasing azole sensitivity [34].
gene mutations are mostly considered to be involved in Flu resistance or higher expression of genes participating in efflux [27][35]. Like other
species, specific
mutations resulted directly in reduced azole susceptibility [36]. Furthermore, genes encoding efflux pumps may play a role too [37][24][28][29]. Analysis confirmed increased expression of the
orthologous gene belonging to ABC superfamily transporters and supposed involvement in multidrug resistance in
together with other transporter genes such as
,
, and
[38]. Study of
and
clinical isolates from 2 hospitals in central Israel revealed that
exhibited higher thermotolerance, virulence in a mouse infection model, and ATP-dependent drug efflux activity than
[37]. Chawdary et al. found 15 missense mutations when aligned to the
wild-type
sequence in
azole-resistant in India, and two variants were found in every resistant strain called Y132F or K143R along 5 mutations that were already identified in azole-resistant
[39][7][36]. Isolates with the K143R mutation were resistant to Vcz [39]. Research of AlJindan and colleagues showed that all selected
isolates were resistant to Flu and sequencing of
revealed the same mutation (F132Y and K143R) in
[25]. Similarly, another only two-hour-lasting assay identified mutations Y132F and K143R in
, and S639F in
HS1, and results were 100% concordant with DNA sequencing results [22]. From the 350 isolates collected in a hospital in India, 90% of
were Flu resistant, and 2% and 8% were resistant to echinocandins and AmB, respectively [7]. Interestingly, mutations in
were markedly related with geographic clades (i.e., F126T in South Africa, Y132F in Venezuela, and Y132F or K143R in India/Pakistan) [40][24]. These variants have similarly been reported in the
gene of
in Columbia [36]. Later, overexpression of
in resistant isolates of
spp. overcame the activity of azole drugs to inhibit the synthesis of lanosterol 14α-demethylase. Molecular experiments have shown that resistant
expressed the increased level of
genes compared to susceptible species; however, until now, this was not examined on susceptible isolates [7].
Furthermore, multidrug resistance in
is driven by prior antifungal prescription in hospitals and subsequent antifungal treatment failures [41][42]. However, the resistance/sensitivity profile depends on the specific clades. This is the case of
isolates in India, which are almost Flu sensitive, whereas a significant level of Flu resistance has been reported in other geographic areas worldwide [26].
2.2. Mechanisms of Resistance to Polyenes
The mechanisms responsible for polyene resistance are poorly understood in
. Generally, whole-genome sequencing of resistant isolates has identified four novel nonsynonymous mutations, emphasizing a probable correlation with AmB resistance. The reduction in ergosterol content in the cellular membrane [21][43] is due to overexpression of several mutated
genes [27]. These mutations included those in genes with homology to the transcription factor
gene of
and a membrane transporter [44]. Munoz and colleagues carried out a comparative transcriptional analysis on a resistant isolate and a sensitive isolate after exposure to AmB [30]. Using RNA sequencing (RNA-seq), it was revealed that 106 genes were induced in response to AmB in the resistant isolate. Most notably, genes involved in the ergosterol biosynthesis pathway were highly induced (
and
), which logically showed an association with the maintenance of cell membrane stability [30]. Rhodes et al. screened 27
isolates from the UK for SNPs in
genes in strains representing reduced sensitivity to AmB. However, variants lighting these differences in drug susceptibility were not found [45].
2.3. Mechanisms of Resistance to Echinocandins
The development of resistance to echinocandins is rare, and they are the first-line therapy drugs against
infections [21][43]. This resistance is typically associated with hot spot mutations in the
gene, which encodes the (1,3)-β-D-glucan synthase enzyme, the target of echinocandins, resulting in lower affinity of the enzyme to the drug [19]. Sequencing of the corresponding hot-spot regions of 38
strains resulted in the discovery that an S639F amino acid substitution was related to pan-echinocandin resistance [7]. Remarkably, this mutation is in the region aligning to the HS1 of
[45]. Indeed, different mutations have also been revealed in the same location in
-resistant isolates including S639Y and S639P, which led to echinocandin resistance in a mouse model in vivo [19]. Identical to other cases of
spp., changes in the
gene leads to caspofungin resistance [27]. On the other side, micafungin-resistant isolates
from patients in Kuwait contained the S639F mutation in hot-spot 1 of
[39]. Multiple studies have reported the isolation of resistant echinocandins across various geographical regions, with the highest levels of resistance reported in India [19][46].
2.4. Mechanisms of Resistance to Flucytosine (5-Fluorocytosine)
Flucytosine, a nucleoside analog, inhibits nucleic acid synthesis. Since this antifungal compound is less used compared to other drugs, the mechanism of resistance is also less understood because fewer studies have been implemented to discover the resistance of
C. auris
to this drug. However, a mutation of
FUR1
was shown to be associated with flucytosine resistance in non-
Candida auris Candida [97], and mutations in the
[47], and mutations in the
FCY2
and
FCY1 genes also seem to be involved in resistance to 5-fluorocytosine [81]. A specific missense mutation of
genes also seem to be involved in resistance to 5-fluorocytosine [27]. A specific missense mutation of
FUR1
causing F211I amino acid substituted in the
FUR1
gene was demonstrated in resistant
C. auris
that had not previously been reported; therefore, more studies are required to confirm the probable mechanisms responsible for the resistance to flucytosine in the tested
C. auris strain [95]. Antifungal drugs used for treatment of
strain [45]. Antifungal drugs used for treatment of
C. auris
infection and mechanism of resistance are summarized in
.
Table 1.
Antifungal drugs commonly used against
C. auris
infection and mechanisms of resistance already reported.
Antifungal Drug Class | Mode of Action | Mechanism of Resistance | Reference(s) | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
Azoles | ||||||||||||
Inhibit the activity of lanosterol 14-α-demethylase enzyme; prevent converting lanosterol to ergosterol, leading to damaging integrity of cell membrane. | ||||||||||||
Overexpression of ATP-binding cassette (ABC) and major facilitator superfamily (MFS) transporters. | ||||||||||||
ERG11 | point mutation: Y132F and K143R. | |||||||||||
Mutation in zinc cluster transcription factors Mrr1 and Tac1. | ||||||||||||
, | ||||||||||||
[ | ||||||||||||
, | ||||||||||||
, | ||||||||||||
] | [ | 7][25][24][28][31][32][33][34][35][38][41][42] |
||||||||||
Polyenes | ||||||||||||
Bind ergosterol molecules in the cytoplasmic membrane; disturb the permeability of cell membrane by formation of pores, causing oxidative damage. | ||||||||||||
Induction of genes associated with sterol biosynthetic process including | ERG1 | , ERG2, ERG6, and ERG13. | ||||||||||
SNPs in different genomic loci related to increased resistance. | ||||||||||||
Echinocandins | ||||||||||||
Inhibit β-(1,3)-D-glucan synthase enzyme, leading to defective cell wall formation. | ||||||||||||
Hot-spot mutation in | FKS1 | gene associated with S639Y, S639P, and S639Y regions and FKS2. |
||||||||||
Flucytosine | Inhibit the nucleic acid synthesis (DNA and RNA) of fungi. | Mutation of FUR1 gene, specifically missense mutation of FUR1 causing F211I amino acid substituted in the FUR1 gene in one flucytosine-resistant isolate. | Mutations in the FCY2, FCY1 genes. |
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