Introduction

In recent years, the emergence of antifungal drug resistance in Nakaseomyces glabratus has posed a significant challenge in the management of vulvovaginitis candidiasis [ 1 ]. In 2003, Krutzman classified C. glabrata in the class Nakaseomyces [ 2 ]. This fungus, a haploid yeast closely related to Saccharomyces cerevisiae, is known to cause yeast infections in humans. Nakaseomyces glabratus complex consists of three species known to cause human diseases, namely C. glabrata sensu stricto, C. nivariensis, and C. bracarensis [ 3 ]. Nakaseomyces glabratus, as a fungal pathogen, exhibits notable resistance to antifungal drugs, which results in considerable difficulties in treating patients with this disease [ 4 ].

It is an opportunistic fungal pathogen responsible for superficial mucosal infections and life-threatening bloodstream infections in immunocompromised individuals. Nakaseomyces glabratus is associated with conditions, such as candidemia, invasive candidiasis, and candiduria [ 5 ]. In addition, N. glabratus is the second most common cause of vulvovaginal candidiasis, particularly in recurrent vulvovaginal candidiasis [ 6 ].

Recently, there have been reports of an increasing prevalence of N. glabratus as a causative agent of fungal infections among patients in various countries, such as Iran [ 6 - 8 ]. Genetic analyses have revealed that mutations in the PDR1 and ERG11 genes significantly contribute to antifungal resistance. However, investigations of candidemia samples in Iran have reported a comparatively low incidence of these mutations, which may be attributable to genetic diversity and variations in treatment protocols [ 5 ,  9 ].

Recent studies have demonstrated upregulation in the expression of resistance genes, such as CDR1, ERG11, and MDR1 in N. glabratus. These genes are associated with drug efflux mechanisms and can lead to intracellular drug accumulation. Understanding these mechanisms can aid in investigating the precise mechanisms of resistance in these fungi, thereby facilitating the development of novel therapeutic approaches.

This study aimed to perform a systematic review of antifungal resistance genes associated with the N. glabratus complex and assess the current state of antifungal resistance gene expression in vulvovaginal candidiasis among the species of this complex.

Materials and Methods

Ethical considerations

The study was approved by Babol University of Medical Sciences and was conducted in compliance with the ethical guidelines with the code IR.MUBABOL.HRI.REC.1402.284.

Search strategy

The present systematic review adhered to international standards and followed the PRISMA checklist. Articles were retrieved from reputable databases, namely "Web of Sciences", "PubMed", and "Scopus" with keywords,  such as "gene resistance" OR "efflux pump gene" OR "ERG gene" OR "CDR gene" OR "PDR gene" OR "MDR gene" OR "FSK gene" OR "gene expression" OR "YPS1" OR "AWP3" OR "EPA1" OR "ERG11" OR "CDR1" OR "CDR2" OR "ERG6" OR "TAC1" OR "PDH1" OR "SNQ2" OR "FAA1" OR "echinocandin resistance gene" OR "drug resistance gene" OR "azole resistance gene" AND "vulvovaginitis" OR "vulvovaginal candidiasis" AND "Torulopsis glabratus" OR "Candida glabrata" OR "C. glabrata" OR "Nakaseomyces glabratus" OR "N. glabratus" OR "C. nivariensis" OR "C. bracarensis" OR "Candida nivariensis" OR "Candida bracarensis". The review included studies conducted from 2000 to 2024, covering the past 24 years to encompass significant global changes.

Study selection

Articles eligible for inclusion were those that investigated the expression of drug resistance genes in N. glabratus associated with vulvovaginitis. Articles were selected through a rigorous selection process, which included the evaluation of samples, sample sizes, non-response rates, and measurement instruments utilized. Furthermore, articles were compared to ensure that confounding variables and other influencing factors were thoroughly examined. Moreover, articles that were not directly related to the research topic were excluded; only articles evaluating antifungal resistance genes in N. glabratus isolated from vulvovaginal candidiasis were included in the review process.

Data extraction and analysis

To systematically handle the studies, all initially searched articles were imported to the EndNote software (version 21.4, Clarivate Analytics, USA). Initially, duplicate documents were removed. The screening process of articles involved the examination of the titles and abstracts of the studies. In this manner, irrelevant articles were eliminated. Subsequently, the full texts of the remaining articles were reviewed to ensure adherence to the inclusion and exclusion criteria.

This process was conducted by two individuals independently. Any discrepancies between these individuals were resolved by a third person, who facilitated the final decision-making process.  Two authors extracted the data independently, including names of authors, year of publication, number of isolates, species, and expression of resistant genes (Figure 1).

Figure 1. PRISMA 2020 flow diagram for a systematic review of Nakaseomyces glabrata drug resistance genes expression in vulvovaginitis.

Results

A comprehensive search of the databases yielded a total of 765 records. After evaluation of the titles, abstracts, and full text of the eligible articles, 762 articles that were not relevant to the objectives of the study were excluded. Subsequently, the EndNote software was employed and a comprehensive review of the full texts of the remaining studies was conducted. Finally, three articles were selected for inclusion in the study, which successfully met all the specified inclusion criteria (Figure 1).

All three studies observed an increase in the expression of genes associated with antifungal resistance in N. glabratus isolated from vulvovaginal candidiasis patients (Table 1). The results indicated the existence of only a significantly limited number of studies on resistance genes in N. glabratus isolated from vulvovaginal candidiasis patients, highlighting the importance of addressing drug resistance.

Lotfali et al. [ 4 ] examined point mutations in the ERG11 gene. According to the results of the quantitative reverse transcription polymerase chain reaction, they found that the mRNA expression level of ERG11 was significantly upregulated in two resistant N. glabratus isolates, compared to the reference strains, with observed fold changes ranging from 1.29 to 3.66.

Gygax et al. [ 10 ] reported a significant elevation in CDR1 and MDR1 gene expression in fluconazole-resistant N. glabratus. These genes are connected to drug efflux mechanisms that can decrease intracellular drug accumulation.

Shi et al. [ 11 ] investigated the overexpression of ERG11, CDR1, and CDR2 in fluconazole-resistant C. nivariensis relative to N. glabratus, revealing a resistance mechanism linked to a comparable efflux pump: CDR1 (11.9 vs. 4.34), CDR2 (10.62 vs. 2.24), and ERG11 (4.27 vs. 2.82). This finding underscores the necessity of evaluation of efflux pump gene expression across different species within the N. glabratus collection (Table 1).

Discussion

Azole antifungal agents, particularly fluconazole and clotrimazole, play a significant role in clinical practice for the management of vulvovaginal candidiasis. Nakaseomyces glabratus is a fungal pathogen that is increasingly recognized as a causative agent of vaginitis [ 12 ]. It ranks as the second most common cause of non-albicans Candida vaginitis after C. albicans. Furthermore, N. glabratus exhibits higher resistance to antifungal drugs, compared to C. albicans, leading to significant treatment challenges [ 10 ,  13 ].

Nakaseomyces glabratus exhibits multiple resistance mechanisms to fluconazole, which include variations in gene regulation, genetic mutations, and cross-resistance among azole derivatives. Reports have shown that there are variations in the virulence factors and antifungal resistance among different species within the N. glabratus complex. For example, it has been reported that N. glabratus sensu stricto is more susceptible to fluconazole, itraconazole, and voriconazole, compared to C. nivariensis [ 14 ].

Catheter-associated candidemia cases caused by fluconazole-resistant C. nivariensis have been documented by Fujita et al. (2007), emphasizing the need for alternative treatments. In blood culture susceptibility tests, echinocandins (caspofungin and micafungin) and flucytosine were found to be the most effective treatments in these cases due to their high sensitivity [ 15 ]. Shi et al. [ 11 ] observed that C. nivariensis strains had higher minimum inhibitory concentrations geometric means of caspofungin, fluconazole, itraconazole, and amphotericin B, compared to C. albicans. Furthermore, conventional antifungals showed a low cure rate in patients with vulvovaginal candidiasis caused by C. nivariensis [ 11 ]. However, Arastehfar et al. (2019) demonstrated that clinical isolates of C. nivariensis were sensitive to azoles, polyenes, and echinocandins [ 16 ].

The mechanisms underlying antifungal resistance in the N. glabratus complex are currently being extensively investigated. Multiple cases have demonstrated that the N. glabratus complex exhibits resistance to azole drugs (Figure 2). These drugs function by inhibition of the 14-α lanosterol demethylase enzyme, which is encoded by the ERG11 gene. The ERG11 gene plays a crucial role in ergosterol biosynthesis. Consequently, mutations in this gene result in cross-resistance to both azoles and polyenes [ 17 ].

Figure 2. Schematic depiction of the overarching mechanism of azole resistance in Nakaseomyces glabratus.

Various studies have reported that antifungal-resistant N. glabratus strains carry mutations in the Pdr1 transcription factor and display increased expression of adenosine triphosphate-binding cassette (ABC)-type efflux pumps, particularly CDR1 and CDR2 [ 18 ,  19 ]. These pumps are responsible for the efflux of small molecules from the cell and are regulated by the TAC1 transcription factor [ 20 ,  21 ].

Mutations in the ERG11 gene can reduce ergosterol production, thus impairing fungal cell function [ 22 ,  23 ]. As a result, the fungus becomes more vulnerable to antifungal agents and the immune system of the host. Mutations in these genes can lead to dysfunction and subsequent cell death [ 24 ]. The glycolysis pathway genes encode enzymes involved in energy production through sugar metabolism, which is vital for the growth and proliferation of N. glabratus [ 25 ].

In addition, the genes associated with the protein synthesis pathway encode enzymes required for protein synthesis, which is essential for cellular functions [ 26 ]. The regulatory genes consist of transcription factor genes, which encode proteins that regulate the expression of other genes, thereby controlling various cellular processes, such as metabolism, growth, and proliferation [ 25 ]. Furthermore, the cell signaling genes encode proteins that facilitate communication between N. glabratus and its environment. Cell signaling is crucial for processes, like adhesion to host cells, invasion, and evasion of the immune system [ 27 ].

Notably, the genes associated with this disease include drug resistance genes, allowing N. glabratus to withstand antifungal medications.  Expression of resistance genes in N. glabratus can be influenced by various factors, including antifungal drug usage, the immune status of the patient, and the specific strain of N. glabratus [ 28 ]. Several genes within N. glabratus play essential roles in its functioning [ 13 ]. Emergence of azole resistance in clinical isolates of N. glabratus has been predominantly associated with the presence of activating mutations in the zinc cluster transcription factor Pdr1 [ 18 ]. These mutations result in differential expression of downstream targets. Rapid occurrence of PDR1 mutations might be attributed to a high frequency of mismatch repair gene MSH2 mutations, which lead to a hypermutable phenotype [ 5 ,  29 ]. Activating mutations exhibit distinct patterns of downstream effector gene expression, except for increased expression of CDR1 and PUP1 [ 30 ].

Several mutations have been identified in the zinc-cluster-containing transcription factor PDR1 in the N. glabratus complex, which support the overexpression of transporters CDR1, CDR2, SNQ2, and PDH1 known for their ability to transport multiple drugs. However, in a study conducted by Lotfali et al.[ 4 ] on azole-resistant N. glabratus isolates, no polymorphisms were observed in the complete sequence alignment of the ERG11 gene. Nevertheless, a mutation in the FKS1 gene resulting in the substitution of serine with leucine at position 642 (S642L) was observed in the isolates.

It is important to note that even C. albicans and N. glabratus isolates without mutations in the ERG11 and HS1 regions of the FKS1 gene may still exhibit resistance to azoles and caspofungin. Moreover, no correlation has been observed between the location of a mutation and altered gene expression. Only three genes with direct binding to Pdr1 have been directly implicated in azole resistance: the ABC transporters CDR1, CDR2, and SNQ2 [ 31 ].

According to Gygax et al. (2008), a ≥3-fold change in the expression of the CDR1 gene of N. glabratus was found to be associated with resistant isolates [ 10 ]. The present investigation revealed two articles specifically addressing this topic. Notably, in their study, Shi et al. (2020) observed that the mRNA expression levels of ERG11, CDR1, and CDR2 genes in C. nivariensis isolates were higher, compared to those in N. glabratus [ 11 ]. This finding suggests that C. nivariensis displays a greater degree of resistance. Furthermore, the expression of resistance genes, such as ERG11, CDR1, and CDR2 were found to be more pronounced in C. nivariensis isolates, compared to N. glabratus (Table 2) [ 11 ].

Recent studies have revealed heightened expression of four major facilitator superfamily (MFS) transporters in clotrimazole-susceptible isolates as opposed to clotrimazole-susceptible clinical isolates [ 32 ]. Perturbing one of these transporters, TPO3, resulted in a moderate augmentation of susceptibility to clotrimazole and fluconazole [ 33 ]. These findings imply a subordinate role for MFS transporters in the development of azole resistance [ 22 ].

Since most strains of N. glabratus are resistant to azoles, echinocandins are a therapeutic measure that has shown some efficacy. Drugs, such as anidulafungin, caspofungin, and micafungin inhibit the enzyme glucan synthase. These drugs inhibit the formation of β-1, 3-D glucan by binding non-competitively to Fks1p and Fks2p subunits of β-1, 3-glucan synthase. Since β-1, 3-D glucan is an integral part of the structure and function of the fungal cell wall, inhibition of its formation causes high cell wall permeability and, consequently, cell lysis. However, increased resistance to these drugs has been observed in N. glabratus complex due to previous exposure to these antifungals. Nevertheless, it seems that since in cases of vulvovaginal candidiasis, low amounts of echinocandin drugs are used, no studies have been conducted in this field.

Nakaseomyces glabratus demonstrates the capacity to thrive with modified plasma membrane sterols, enabling the organism to elude azole treatment. Additionally, N. glabratus is capable of assimilating exogenous sterols, regardless of whether the ergosterol biosynthetic pathway is obstructed or under normal conditions in wild-type strains [ 34 ]. Aus1p has been identified as the sterol transporter that is responsible for the tolerance to azoles in the presence of exogenous sterols. Azole resistance in N. glabratus has been linked to the emergence of petite mutants, which are characterized by mitochondrial dysfunction and respiratory deficiency [ 35 ].

Understanding the regulation of these genes is crucial for the development of novel antifungal therapies and the prevention and treatment of N. glabratus-induced vaginitis.

A limitation of this study was that the available literature in this field was insufficient for conducting a meta-analysis that would enable more robust conclusions. Since the present study aimed to find drug resistance genes only in N. glabratus isolates from vulvovaginitis, only three studies could be evaluated.

Conclusion

Significance of understanding the role of CDR1 gene in fluconazole resistance cannot be overstated. This gene is central to the development of resistance and will continue to shape the landscape of antifungal therapy and patient management in the years to come. Based on the findings of the texts investigated in this study, the gene expression of azole resistance in N. glabratus was associated with vulvovaginitis candidiasis.

The key insights include a growing trend of resistance in N. glabratus, the identification of specific mutations in the ERG11 and FKS genes correlated with resistance, and the clinical implications of the treatment of infections caused by N. glabratus complex, such as C. nivariensis. It is clear from the compiled evidence that future efforts must be geared toward enhancing our knowledge base, improving diagnostic capabilities, and fostering the development of new antifungal agents.

Acknowledgments

The authors consider it necessary to acknowledge the Vice-Chancellor of Research and Technology of Babol University of Medical Sciences, Babol, Iran.

Authors’ Contributions

F. Z. R. G. contributed to conceptualization, investigation, writing the original draft, methodology, validation, data curation, and software usage. F. K. contributed to software usage, formal analysis, investigation, writing, review, edition, and visualization. S. A. G. contributed to conceptualization, methodology, validation, and data curation. M. T. A. contributed to the investigation, writing, review, edition, and visualization. S. M. O. contributed to visualization, validation, resources, writing, review, edition, project administration, and supervision. All authors have read and approved the final manuscript.

Conflicts of Interest

The authors report no conflicts of interest. The authors alone are responsible for the content and the writing of the paper.

Financial Disclosure

None.

References

1. Bradfield Strydom M, Khan S, Walpola RL, Ware RS, Tiralongo E. Interplay of the microbiome and antifungal therapy in recurrent vulvovaginal candidiasis (RVVC): A narrative review. J Med Microbiol. 2023; 72(5):001705.
2. Denning DW. Renaming Candida glabrata-A case of taxonomic purity over clinical and public health pragmatism. PLoS Pathog. 2024; 20(3):e1012055.
3. Li J, Shan Y, Fan S, Liu X. Prevalence of Candida nivariensis and Candida bracarensis in vulvovaginal Candidiasis. Mycopathologia. 2014; 178(3-4):279-83.
4. Lotfali E, Erami M, Fattahi M, Nemati H, Ghasemi Z, Mahdavi E. Analysis of molecular resistance to azole and echinocandin in Candida species in patients with vulvovaginal candidiasis. Curr Med Mycol. 2022; 8(2):1-7.
5. Arastehfar A, Daneshnia F, Zomorodian K, Najafzadeh MJ, Khodavaisy S, Zarrinfar H, et al. Low Level of Antifungal Resistance in Iranian Isolates of Candida glabrata Recovered from Blood Samples in a Multicenter Study from 2015 to 2018 and Potential Prognostic Values of Genotyping and Sequencing of PDR1. Antimicrob Agents Chemother. 2019; 63(7): e02503-18.
6. Jannati B, Pourdad A, Izadjoo A, Zarrinfar H, Najafzadeh MJ, Fata A. The Prevalence of Non-albicans Candida and Candida Mixed-species in Vulvovaginal Candidiasis in Northeast Iran. Clin Exp Obstet Gynecol. 2024; 51(3):77.
7. Zarrinfar H, Kord Z, Fata A. High incidence of azole resistance among Candida albicans and C. glabrata isolates in Northeastern Iran. Curr Med Mycol. 2021; 7(3):18-21.
8. Waikhom SD, Afeke I, Kwawu GS, Mbroh HK, Osei GY, Louis B, et al. Prevalence of vulvovaginal candidiasis among pregnant women in the Ho municipality, Ghana: species identification and antifungal susceptibility of Candida isolates. BMC Pregnancy Childbirth. 2020; 20(1):266.
9. Al-Baqsami ZF, Ahmad S, Khan Z. Antifungal drug susceptibility, molecular basis of resistance to echinocandins and molecular epidemiology of fluconazole resistance among clinical Candida glabrata isolates in Kuwait. Sci Rep. 2020; 10(1):6238.
10. Gygax SE, Vermitsky JP, Chadwick SG, Self MJ, Zimmerman JA, Mordechai E, et al. Antifungal resistance of Candida glabrata vaginal isolates and development of a quantitative reverse transcription-PCR-based azole susceptibility assay. Antimicrob Agents Chemother. 2008; 52(9):3424-3426.
11. Shi Y, Zhu Y, Fan S, Vitagliano A, Liu X, Liao Y, et al. Clinical Characteristics and Antifungal Susceptibility of Candida nivariensis from Vulvovaginal Candidiasis. Gynecol Obstet Invest. 2020; 85(1):88-93.
12. Zhang JY, Liu JH, Liu FD, Xia YH, Wang J, Liu X, et al. Vulvovaginal candidiasis: species distribution, fluconazole resistance and drug efflux pump gene overexpression. Mycoses. 2014; 57(10):584-91.
13. Beardsley J, Kim HY, Dao A, Kidd S, Alastruey-Izquierdo A, Sorrell TC, et al. Candida glabrata (Nakaseomyces glabrata): A systematic review of clinical and microbiological data from 2011 to 2021 to inform the World Health Organization Fungal Priority Pathogens List. Med Mycol. 2024; 62(6):myae041.
14. Hernando-Ortiz A, Mateo E, Ortega-Riveros M, De-la-Pinta I, Quindós G, Eraso E. Caenorhabditis elegans as a model system to assess Candida glabrata, Candida nivariensis, and Candida bracarensis virulence and antifungal efficacy. Antimicrob Agents Chemother. 2020; 64(10):e00824-20.
15. Fujita S-i, Senda Y, Okusi T, Ota Y, Takada H, Yamada K, et al. Catheter-related fungemia due to fluconazole-resistant Candida nivariensis. J Clin Microbiol. 2007; 45(10):3459-61.
16. Arastehfar A, Daneshnia F, Salehi M-R, Zarrinfar H, Khodavaisy S, Haas P-J, et al. Molecular characterization and antifungal susceptibility testing of Candida nivariensis from blood samples–an Iranian multicentre study and a review of the literature. J Med Microbiol. 2019; 68(5):770-777.
17. Liu XH, Meng YF, Nie XJ, Li XY, Tan LY, Chen LM. Candida Exerts Fluconazole-Resistant Effect via Regulating the Expression of CDR and ERG11 in Patients with Vaginitis. Lat Am J Pharm. 2021; 40(8):1923-30.
18. Whaley SG, Zhang Q, Caudle KE, Rogers PD. Relative Contribution of the ABC Transporters Cdr1, Pdh1, and Snq2 to Azole Resistance in Candida glabrata. Antimicrob Agents Chemother. 2018; 62(10): e01070-18.
19. Rocha DAS, Sa LFR, Pinto ACC, Junqueira ML, Silva EMD, Borges RM, et al. Characterisation of an ABC transporter of a resistant Candida glabrata clinical isolate. Mem Inst Oswaldo Cruz. 2018; 113(4):e170484.
20. El Said M, Badawi H, Gamal D, Salem D, Dahroug H, El-Far A. Detection of ERG11 gene in fluconazole resistant urinary Candida isolates. Egypt J Immunol. 2022; 29(4):134-147.
21. Zare-Bidaki M, Maleki A, Ghanbarzadeh N, Nikoomanesh F. Expression pattern of drug-resistance genes ERG11 and TAC1 in Candida albicans Clinical isolates. Mol Biol Rep. 2022; 49(12):11625-33.
22. Vu BG, Moye-Rowley WS. Azole-Resistant Alleles of ERG11 in Candida glabrata Trigger Activation of the Pdr1 and Upc2A Transcription Factors. Antimicrob Agents Chemother. 2022; 66(3):e02098-21.
23. Pam VK, Akpan JU, Oduyebo OO, Nwaokorie FO, Fowora MA, Oladele RO, et al. Fluconazole susceptibility and ERG11 gene expression in vaginal Candida species isolated from Lagos Nigeria. Int J Mol Epidemiol Genet. 2012; 3(1):84-90.
24. Frias-De-Leon MG, Hernandez-Castro R, Conde-Cuevas E, Garcia-Coronel IH, Vazquez-Aceituno VA, Soriano-Ursua MA, et al. Candida glabrata Antifungal Resistance and Virulence Factors, a Perfect Pathogenic Combination. Pharmaceutics. 2021; 13(10):1529.
25. Yoo JI, Choi CW, Kim HS, Yoo JS, Jeong YH, Lee YS. Proteomic Analysis of Cellular and Membrane Proteins in Fluconazole-Resistant Candida glabrata. Osong Public Health Res Perspect. 2012; 3(2):74-78.
26. Sanguinetti M, Posteraro B, Fiori B, Ranno S, Torelli R, Fadda G. Mechanisms of azole resistance in clinical isolates of Candida glabrata collected during a hospital survey of antifungal resistance. Antimicrob Agents Chemother. 2005; 49(2):668-79.
27. Salgado RC, Fonseca DLM, Marques AHC, da Silva Napoleao SM, Franca TT, Akashi KT, et al. The network interplay of interferon and Toll-like receptor signaling pathways in the anti-Candida immune response. Sci Rep. 2021; 11(1):20281.
28. Healey KR, Jimenez Ortigosa C, Shor E, Perlin DS. Genetic Drivers of Multidrug Resistance in Candida glabrata. Front Microbiol. 2016; 7
29. Conway TP, Simonicova L, Moye-Rowley WS. Overlapping coactivator function is required for transcriptional activation by the Candida glabrata Pdr1 transcription factor. Genetics. 2024; 228(1): iyae115.
30. Rodrigues CF, Rodrigues ME, Silva S, Henriques M. Candida glabrata Biofilms: How Far Have We Come? J Fungi (Basel). 2017; 3(1):11.
31. Sanglard D, Ischer F, Calabrese D, Majcherczyk PA, Bille J. The ATP binding cassette transporter gene CgCDR1 from Candida glabrata is involved in the resistance of clinical isolates to azole antifungal agents. Antimicrob Agents Chemother. 1999; 43(11):2753- 2765.
32. Paul S, Bair TB, Moye-Rowley WS. Identification of genomic binding sites for Candida glabrata Pdr1 transcription factor in wild-type and rho0 cells. Antimicrob Agents Chemother. 2014; 58(11):6904- 6912.
33. Bernardo RT, Cunha DV, Wang C, Pereira L, Silva S, Salazar SB, et al. The CgHaa1-Regulon Mediates Response and Tolerance to Acetic Acid Stress in the Human Pathogen Candida glabrata. G3 (Bethesda). 2017; 7(1):1-18.
34. Salazar SB, Pinheiro MJF, Sotti-Novais D, Soares AR, Lopes MM, Ferreira T, et al. Disclosing azole resistance mechanisms in resistant Candida glabrata strains encoding wild-type or gain-of-function CgPDR1 alleles through comparative genomics and transcriptomics. G3 (Bethesda). 2022; 12(7):jkac110.
35. Li QQ, Tsai HF, Mandal A, Walker BA, Noble JA, Fukuda Y, et al. Sterol uptake and sterol biosynthesis act coordinately to mediate antifungal resistance in Candida glabrata under azole and hypoxic stress. Mol Med Rep. 2018; 17(5):6585- 6597.