Molecular Mechanisms Associated with Antifungal Resistance in Pathogenic Candida Species
Abstract
:1. Introduction
1.1. Candidiasis
1.1.1. Candida Species of Interest
1.1.2. Candida auris
1.2. Primary/Intrinsic Resistance vs. Secondary/Acquired Resistance
1.3. Standardized Measures of Susceptibility Testing
1.4. Geographic Influence on Rates of Antifungal Resistance
2. Antifungal Classes and Frequency of Resistance
2.1. Azoles
2.2. Polyenes
2.3. Echinocandins
2.4. 5FC
3. The Ergosterol Biosynthesis Pathway and Antifungal Resistance
3.1. ERG11
3.2. Mutations in Transcriptional Regulators
3.3. Other ERG Genes and Toxic Diol Formation
4. Cell Membrane Proteins and Antifungal Resistance
4.1. Drug Efflux Pump/Transporter Genes and Resistant Mutations
4.2. Transcriptional Regulators of Transporter Genes
4.3. Post-Translational Regulation of Transporter Genes
5. The Cell Wall Biosynthesis Pathway and Antifungal Resistance
5.1. FKS1 and FKS2 Sequence Mutations
5.2. Transcriptional Regulators of fks Genes
5.3. Protein Analysis Associated with Echinocandin Resistance
6. The Nucleic Acid Biosynthesis Pathway and Antifungal Resistance
7. Biofilm Formation and Antifungal Resistance
7.1. Biofilm Formation during Antifungal Treatment
7.2. The Roles of β-1,3 Glucan and Biofilm-Associated Antifungal Resistance
7.3. Relevant Antifungal Resistance Genes in Biofilm-Associated Candida Infections
8. Future Directions
Author Contributions
Funding
Conflicts of Interest
References
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Antifungal Class | Drug Name | Fungal Species | CLSI MIC Breakpoints (µg/mL) | EUCAST MIC Breakpoints (µg/mL) | ||||||
---|---|---|---|---|---|---|---|---|---|---|
S | I | SSD | R | S | I | SSD | R | |||
Azole | Fluconazole (FLZ) | C. albicans | ≤2 | - | 4 | ≥8 | ≤2 | 4 | - | >4 |
C. dubliniensis | - | - | - | - | ≤2 | 4 | - | >4 | ||
N. glabrata | - | - | ≤32 | ≥64 | ≤0.001 | ≤16 | - | >16 | ||
P. kudriavzevii | - | - | - | - | - | - | - | - | ||
C. parapsilosis | ≤2 | 4 | ≥8 | ≤2 | 4 | - | >4 | |||
C. tropicalis | ≤2 | 4 | ≥8 | ≤2 | 4 | - | >4 | |||
Voriconazole (VOR) | C. albicans | ≤0.12 | 0.25–0.5 | - | ≥1 | ≤0.06 | 0.125–0.25 | - | >0.25 | |
C. dubliniensis | ≤0.06 | 0.125–0.25 | - | >0.25 | ||||||
N. glabrata | - | - | - | - | - | - | - | - | ||
P. kudriavzevii | ≤0.5 | 1 | - | ≥2 | - | - | - | - | ||
C. parapsilosis | ≤0.12 | 0.25–0.5 | - | ≥1 | ≤0.125 | 0.25 | - | >0.25 | ||
C. tropicalis | ≤0.12 | 0.25–0.5 | - | ≥1 | ≤0.125 | 0.25 | - | >0.25 | ||
Posaconazole | C. albicans | - | - | - | - | ≤0.06 | - | - | >0.06 | |
C. dubliniensis | - | - | - | - | ≤0.06 | - | - | >0.06 | ||
C. parapsilosis | - | - | - | - | ≤0.06 | - | - | >0.06 | ||
C. tropicalis | - | - | - | - | ≤0.06 | - | - | >0.06 | ||
Itraconazole | C. albicans | - | - | - | - | ≤0.06 | - | - | >0.06 | |
C. dubliniensis | - | - | - | - | ≤0.06 | - | - | >0.06 | ||
C. parapsilosis | - | - | - | - | ≤0.125 | - | - | >0.125 | ||
C. tropicalis | - | - | - | - | ≤0.125 | - | - | >0.125 | ||
Echinocandin | Caspofungin | C. albicans | ≤0.25 | 0.5 | - | ≥1 | - | - | - | - |
N. glabrata | ≤0.12 | 0.25 | - | ≥0.5 | - | - | - | - | ||
M. guilliermondii | ≤2 | 4 | - | ≥8 | - | - | - | - | ||
P. kudriavzevii | ≤0.25 | 0.5 | - | ≥1 | - | - | - | - | ||
C. parapsilosis | ≤2 | 4 | - | ≥8 | - | - | - | - | ||
C. tropicalis | ≤0.25 | 0.5 | - | ≥1 | - | - | - | - | ||
Anidulafungin | C. albicans | ≤0.25 | 0.5 | - | ≥1 | ≤0.03 | - | - | >0.03 | |
N. glabrata | ≤0.12 | 0.25 | ≥0.5 | ≤0.06 | - | - | >0.06 | |||
M. guilliermondii | ≤2 | 4 | ≥8 | - | - | - | - | |||
P. kudriavzevii | ≤0.25 | 0.5 | ≥1 | ≤0.06 | - | - | >0.06 | |||
C. parapsilosis | ≤2 | 4 | ≥8 | ≤4 | - | - | >4 | |||
C. tropicalis | ≤0.25 | 0.5 | ≥1 | ≤0.06 | - | - | >0.06 | |||
Micafungin | C. albicans | ≤0.25 | 0.5 | - | ≥1 | ≤0.016 | - | - | >0.016 | |
N. glabrata | ≤0.06 | 0.12 | - | ≥0.25 | ≤0.03 | - | - | >0.03 | ||
M. guilliermondii | ≤2 | 4 | - | ≥8 | - | - | - | - | ||
P. kudriavzevii | ≤0.25 | 0.5 | - | ≥1 | - | - | - | - | ||
C. parapsilosis | ≤2 | 4 | - | ≥8 | ≤2 | - | - | >2 | ||
C. tropicalis | ≤0.25 | 0.5 | - | ≥1 | - | - | - | - | ||
Polyene | Amphotericin B | C. albicans | ≤1 | - | - | >1 | ||||
C. dubliniensis | ≤1 | - | - | >1 | ||||||
N. glabrata | ≤1 | - | - | >1 | ||||||
P. kudriavzevii | ≤1 | - | - | >1 | ||||||
C. parapsilosis | ≤1 | - | - | >1 | ||||||
C.tropicalis | ≤1 | - | - | >1 | ||||||
C. auris | Tentative breakpoints based on a mouse model reported by the CDC (2020): S (≤1), R (≥2) | |||||||||
Nystatin | Candida | CLSI and EUCAST MIC breakpoints unavailable.Broth microdilution estimates based on Brito et al., 2011: S (≤4), I (8–32), R (≥64) |
Gene | Candida Species | Mutation | Type of Mutation | Antifungal Resistance | Location | Isolate Type | Ref. |
---|---|---|---|---|---|---|---|
ERG11 (lanosterol 14a-demethylase) | C. albicans | Hotspot regions: aa105–165, 266–287 and 405–488 | Substitution | Azole | USA | Clinical | [36] |
A61V, S405F, G448E, F449S, G464S, R467K and I471T | Non-synonymous substitution | Fluconazole | China | Clinical | [86] | ||
Y132H, Y132F, K143R and K143Q | Non-synonymous substitution | Fluconazole and voriconazole | China | Clinical | [86,89] | ||
A114S and Y257H | Non-synonymous substitution | Fluconazole and voriconazole | China | Clinical | [86,90] | ||
T315A, Y118A, Y18F and Y118T | Non-synonymous substitution | Fluconazole | - | Lab-created | [91,92] | ||
K128T | Non-synonymous substitution | Likely no effect | China | Clinical | [86,93] | ||
D116E and E266D | Non-synonymous substitution | No effect on protein function or resistance | USA | Clinical | [36] | ||
C. auris | F126T, Y132F and K143R | Non-synonymous substitution | Fluconazole | South Africa, Venezuela, India | Clinical | [28] | |
N. glabrata | C108G, C423T and A1581G | Synonymous substitution | No effect | Brazil | Clinical | [94] | |
T768C, A1023G and T1557A | Synonymous substitution | No effect | Slovakia | Clinical | [95] | ||
E502V | Non-synonymous substitution | No effect | Slovakia | Clinical | [96] | ||
P. kudriavzevii | G524R | Non-synonymous substitution | No effect on protein function or resistance | Brazil | Clinical | [94] | |
Y166S | Non-synonymous substitution | Voriconazole | Brazil | Clinical | [94] | ||
C. tropicalis | Y132F | Missense | Fluconazole | Brazil | Clinical | [97] | |
K143R | Non-synonymous substitution | Fluconazole, voriconazole and itraconazole | Brazil | Clinical | [98] | ||
ERG3 (C5 sterol desaturase) | N. glabrata | Q139A | Non-synonymous substitution | Fluconazole | Korea | Clinical | [99] |
UPC2 (TF, regulates most ERG genes) | C. albicans | G648D, G648S, A643T, Y642F, A646V and W478C | GOF substitution | Fluconazole | USA | Clinical | [100] |
A643V | GOF substitution | Fluconazole | USA | Clinical | [100] | ||
G307S and G448E | GOF substitution | Fluconazole | Germany | Clinical | [101] |
Gene | Candida Species | Mutation | Type of Mutation | Antifungal Resistance | Location | Isolate Type | Ref. |
---|---|---|---|---|---|---|---|
CDR1 + CDR2 (ABC-Ts) | C. albicans | Chr 3 trisomy | Increased cdr1 and cdr2 copy numbers | Azole | - | In vitro | [124] |
MLT1 (ABC-T) | C. albicans | K710A | Loss of function | Reduced azole resistance | - | In vitro | [123] |
F765Δ | Loss of function | Reduced azole resistance | - | In vitro | [123] | ||
TAC1 (TF, regulates CDR1, CDR2 and PDR16) | C. albicans | T225A, V736A, N972D, N977D, G980E and G980W | GOF substitution | Azole | USA | Clinical | [125] |
C. auris | K143R, F214S, R495G and A640V | Non-synonymous substitution | Fluconazole | USA | Clinical/ in vitro | [126] | |
MRR1 (TF, regulates MDR1) | C. albicans | P683S and P683H | GOF substitution | Azole | Germany | Clinical | [101,127] |
C. dubliniensis | T374I, S595Y and C866Y | GOF substitution | Azole | Ireland | Clinical | [128,129,130] | |
T965∆ and (D987-I998)∆ | Deletion | Azole | Ireland | Clinical | [128] | ||
PDR16 (phosphatidylinositol transfer protein) | N. glabrata | ∆pdr16 | Gene deletion | Reduced resistance to fluconazole, itraconazole and ketoconazole miconazole | - | In vitro | [131] |
PDR1 (TF, regulates CDR1, SNQ2, PDH1 and QDR2) | N. glabrata | Hotspot regions: 312–382, 800–1107 and 539–632 | GOF substitution | Azole | Italy, Switzerland, France and Japan | Clinical | [35,132] |
L328F, R376W, D1082G, T588A, T607S, E1083Q, Y584C, D876Y, L280F, N691D, S316I, D261G, R293I, R592S, G583S, S343F and R376G | GOF substitution | Fluconazole | Italy, Switzerland, France and Japan | Clinical | [132] |
Gene | Candida Species | Mutation | Type of Mutation | Antifungal Resistance | Location | Isolate Type | Ref. |
---|---|---|---|---|---|---|---|
FKS1 (β1–3 glucan synthase) | C. albicans | Hotspot regions: aa 637–654 and 1345–1365 | Non-synonymous substitution | Echinocandin | - | Clinical | [74,162] |
S645F | Non-synonymous substitution | Echinocandin | USA | Clinical | [170] | ||
C. auris | F635Y, F635L, S639F and R1354S | Non-synonymous substitution | Echinocandin | India | In vitro/ in vivo | [168] | |
N. glabrata | F625C and S629P | Non-synonymous substitution | Echinocandin | - | Clinical/ in vitro | [171,172] | |
F625∆ | Deletion | Echinocandin | - | Clinical/ in vitro | [171,172] | ||
P. kudriavzevii | F655C | Non-synonymous substitution | Echinocandin | USA | Clinical | [166] | |
C. parapsilosis | P660A | Non-synonymous substitution | Echinocandin | - | All species members | [161] | |
FKS2 (β1–3 glucan synthase) | N. glabrata | F659S and F659V | Non-synonymous substitution | Echinocandin | USA | Clinical | [158,159,173] |
F659∆ | Deletion | Echinocandin | USA | Clinical | [158,159,173] | ||
S663P and S663F | Non-synonymous substitution | Echinocandin | USA | Clinical | [171,172] | ||
E655G, E655K, P667H and P667T | Non-synonymous substitution | Echinocandin | USA | Clinical | [171,172] | ||
R1378S and R1378G | Non-synonymous substitution | Echinocandin | USA | Clinical | [171,172] |
Gene | Candida Species | Mutation | Type of Mutation | Antifungal Resistance | Location | Isolate Type | Ref. |
---|---|---|---|---|---|---|---|
FCA1/FCY1 (cytosine deaminase) | C. albicans | G28D and S29L | LOF substitution | 5FC | UK | Clinical | [197] |
C. dubliniensis | S29L | Non-synonymous substitution | 5FC | Egypt and Saudi Arabia | Clinical | [190] | |
N. glabrata | A15D, G11D and W148R | Non-synonymous substitution | 5FC | - | In vitro | [201] | |
FCY2 (cytosine permease) | C. albicans | A176G | LOF substitution | 5FC | UK | Clinical | [197] |
C. tropicalis | G145T | Non-synonymous substitution | 5-FC | Taiwan | Clinical | [200] | |
FUR1 (uracil phosphoribosyltransferase (UPRT)) | C. albicans | C101R | LOF substitution | 5FC | Multiple countries | Clinical | [196,197] |
N. glabrata | G190D | LOF substitution | 5FC | France | Clinical | [195] | |
I83K and D193G | LOF substitution | 5FC/5FU | - | In vitro | [201,202] | ||
∆G73-V81 | LOF Deletion | 5FC/5FU | - | In vitro | [201,202] | ||
MSH2 (DNA mismatch repair) | N. glabrata | V239L | Non-synonymous substitution | Fluconazole or echinocandin | Multiple countries | Clinical | [35] |
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Czajka, K.M.; Venkataraman, K.; Brabant-Kirwan, D.; Santi, S.A.; Verschoor, C.; Appanna, V.D.; Singh, R.; Saunders, D.P.; Tharmalingam, S. Molecular Mechanisms Associated with Antifungal Resistance in Pathogenic Candida Species. Cells 2023, 12, 2655. https://doi.org/10.3390/cells12222655
Czajka KM, Venkataraman K, Brabant-Kirwan D, Santi SA, Verschoor C, Appanna VD, Singh R, Saunders DP, Tharmalingam S. Molecular Mechanisms Associated with Antifungal Resistance in Pathogenic Candida Species. Cells. 2023; 12(22):2655. https://doi.org/10.3390/cells12222655
Chicago/Turabian StyleCzajka, Karolina M., Krishnan Venkataraman, Danielle Brabant-Kirwan, Stacey A. Santi, Chris Verschoor, Vasu D. Appanna, Ravi Singh, Deborah P. Saunders, and Sujeenthar Tharmalingam. 2023. "Molecular Mechanisms Associated with Antifungal Resistance in Pathogenic Candida Species" Cells 12, no. 22: 2655. https://doi.org/10.3390/cells12222655
APA StyleCzajka, K. M., Venkataraman, K., Brabant-Kirwan, D., Santi, S. A., Verschoor, C., Appanna, V. D., Singh, R., Saunders, D. P., & Tharmalingam, S. (2023). Molecular Mechanisms Associated with Antifungal Resistance in Pathogenic Candida Species. Cells, 12(22), 2655. https://doi.org/10.3390/cells12222655