Correction: Chen et al. Mechanisms of Azole Resistance and Trailing in Candida tropicalis Bloodstream Isolates. J. Fungi 2021, 7, 612

ABSTRACT Azole resistance has been insufficiently investigated in the yeast Candida tropicalis. Here we determined the molecular mechanisms responsible for azole resistance in a clinical isolate of this pathogenic yeast. Antifungal susceptibility testing performed by a disk diffusion method showed resistance or markedly decreased susceptibility to azoles, which was confirmed by determination of MICs. Considering the relationship between azole susceptibility and the respiration reported for other yeast species, the respiratory activity of this isolate was investigated. Flow cytometry using rhodamine 123 and oxygraphy demonstrated an increased respiratory activity, which was not linked to an overexpression or increased number of copies of the mitochondrial genome. Among previously described resistance mechanisms, an increased activity of efflux pumps was investigated by flow cytometry using rhodamine 6G. However, the efflux of rhodamine 6G was lower in the resistant isolate than in susceptible ones. Likewise, real-time reverse transcription-PCR quantification of the expression of C. tropicalis MDR1 (CtMDR1), which encodes an efflux protein belonging to the major facilitator superfamily, did not show overexpression of this gene. In contrast, the resistant isolate overexpressed the CtERG11 gene coding for lanosterol 14α-demethylase. This was in agreement with the larger amount of ergosterol found in this isolate. Moreover, sequencing of CtERG11 showed a point mutation leading to a tyrosine substitution in the protein sequence, which might lead to decreased binding affinity for azoles. In conclusion, overexpression of CtERG11 associated with a missense mutation in this gene seemed to be responsible for the acquired azole resistance of this clinical isolate.

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Virulence Factors and Azole-Resistant Mechanism of Candida Tropicalis Isolated From Candidemia

10.21203/rs.3.rs-377398/v1 ◽

2021 ◽

Author(s):

Elahe Sasani ◽

Sadegh Khodavaisy ◽

Sassan Rezaie ◽

Mohammadreza Salehi ◽

Muhammad Getso ◽

...

Keyword(s):

Virulence Factors ◽

Candida Tropicalis ◽

Biofilm Formation ◽

Molecular Mechanisms ◽

Antifungal Susceptibility ◽

Cell Surface Hydrophobicity ◽

Surface Hydrophobicity ◽

Azole Resistance ◽

Virulence Determinants ◽

Fluconazole Resistant

Abstract Background Virulence factors intensify the pathogenicity of Candida species in candidemia. Limited knowledge exists regarding the azole-resistant mechanism and virulence factors of Candida tropicalis. Consequently, we aimed to evaluate the virulence factors and the molecular mechanisms of azole resistance among C. tropicalis isolated from bloodstream infection. Materials and methods Forty-five C. tropicalis isolates recovered from candidemia patients were evaluated for virulence factors, including extracellular enzymatic activities, cell surface hydrophobicity (CHS), and biofilm formation. Antifungal susceptibility pattern and expression level of ERG11, UPC2, MDR1, and CDR1 genes of eight azole resistance C. tropicalis isolates were assessed. Results The isolates expressed different frequencies of virulence determinants as follows: coagulase 4 (8.9%), phospholipase 4 (8.9 %), proteinase 31 (68.9 %), CSH 43 (95.6 %), esterase 43 (95.6 %), hemolysin 44 (97.8%), and biofilm formation 45 (100%). All the isolates were susceptible to amphotericin B and showed the highest resistance to voriconazole. The high expression of ERG11 and UPC2 genes in fluconazole-resistant C. tropicalis isolates were observed. Conclusion C. tropicalis isolated from candidemia patients extensively displayed capacities for biofilm formation, hemolysis, esterase activity, and hydrophobicity. In addition, the overexpression of ERG11 and UPC2 genes can be considered as one of the possible mechanisms of azole resistance.

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Resistance Mechanisms and Clinical Features of Fluconazole-Nonsusceptible Candida tropicalis Isolates Compared with Fluconazole-Less-Susceptible Isolates

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02652-15 ◽

2016 ◽

Vol 60 (6) ◽

pp. 3653-3661 ◽

Cited By ~ 27

Author(s):

Min Ji Choi ◽

Eun Jeong Won ◽

Jong Hee Shin ◽

Soo Hyun Kim ◽

Wee-Gyo Lee ◽

...

Keyword(s):

Amino Acid ◽

Clinical Features ◽

Candida Tropicalis ◽

Resistance Mechanisms ◽

Therapeutic Failure ◽

Clinical Isolates ◽

Azole Resistance ◽

Amino Acid Substitutions ◽

Content Type ◽

Expression Levels

We investigated the azole resistance mechanisms and clinical features of fluconazole-nonsusceptible (FNS) isolates ofCandida tropicalisrecovered from Korean surveillance cultures in comparison with fluconazole-less-susceptible (FLS) isolates. Thirty-five clinical isolates ofC. tropicalis, comprising 9 FNS (fluconazole MIC, 4 to 64 μg/ml), 12 FLS (MIC, 1 to 2 μg/ml), and 14 control (MIC, 0.125 to 0.5 μg/ml) isolates, were assessed.CDR1,MDR1, andERG11expression was quantified, and theERG11andUPC2genes were sequenced. Clinical features of 16 patients with FNS or FLS bloodstream isolates were analyzed. Both FNS and FLS isolates had >10-fold higher mean expression levels ofCDR1,MDR1, andERG11genes than control isolates (Pvalues of <0.02 for all). When FNS and FLS isolates were compared, FNS isolates had 3.4-fold higher meanERG11expression levels than FLS isolates (P= 0.004), but there were no differences in those ofCDR1orMDR1. Of all 35 isolates, 4 (2 FNS and 2 FLS) and 28 (8 FNS, 11 FLS, and 9 control) isolates exhibited amino acid substitutions in Erg11p and Upc2p, respectively. Both FNS and FLS bloodstream isolates were associated with azole therapeutic failure (3/4 versus 4/7) or uncleared fungemia (4/6 versus 4/10), but FNS isolates were identified more frequently from patients with previous azole exposure (6/6 versus 3/10;P= 0.011) and immunosuppression (6/6 versus 3/10;P= 0.011). These results reveal that the majority of FNSC. tropicalisisolates show overexpression ofCDR1,MDR1, andERG11genes, and fungemia develops after azole exposure in patients with immunosuppression.

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Mechanisms of azole resistance in 52 clinical isolates of Candida tropicalis in China

Journal of Antimicrobial Chemotherapy ◽

10.1093/jac/dks481 ◽

2012 ◽

Vol 68 (4) ◽

pp. 778-785 ◽

Cited By ~ 73

Author(s):

C. Jiang ◽

D. Dong ◽

B. Yu ◽

G. Cai ◽

X. Wang ◽

...

Keyword(s):

Candida Tropicalis ◽

Clinical Isolates ◽

Azole Resistance

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Mechanisms of Azole Resistance and Trailing in Candida tropicalis Bloodstream Isolates

Journal of Fungi ◽

10.3390/jof7080612 ◽

2021 ◽

Vol 7 (8) ◽

pp. 612

Author(s):

Pao-Yu Chen ◽

Yu-Chung Chuang ◽

Un-In Wu ◽

Hsin-Yun Sun ◽

Jann-Tay Wang ◽

...

Keyword(s):

Candida Tropicalis ◽

Molecular Mechanisms ◽

Clonal Complex ◽

Geometric Mean ◽

Azole Resistance ◽

Expression Levels ◽

Genes Encoding ◽

The Difference ◽

Residual Growth

Objectives: Azole-resistant Candida tropicalis has emerged in Asia in the context of its trailing nature, defined by residual growth above minimum inhibitory concentrations (MICs). However, limited investigations in C. tropicalis have focused on the difference of genotypes and molecular mechanisms between these two traits. Methods: Sixty-four non-duplicated C. tropicalis bloodstream isolates collected in 2017 were evaluated for azole MICs by the EUCAST E.def 7.3.1 method, diploid sequence type (DST) by multilocus sequencing typing, and sequences and expression levels of genes encoding ERG11, its transcription factor, UPC2, and efflux pumps (CDR1, CDR2 and MDR1). Results: Isavuconazole showed the highest in vitro activity and trailing against C. tropicalis, followed by voriconazole and fluconazole (geometric mean [GM] MIC, 0.008, 0.090, 1.163 mg/L, respectively; trailing GM, 27.4%, 20.8% and 19.5%, respectively; both overall p < 0.001). Fourteen (21.9%) isolates were non-WT to fluconazole/voriconazole, 12 of which were non-WT to isavuconazole and clustered in clonal complex (CC) 3. Twenty-five (39.1%) isolates were high trailing WT, including all CC2 isolates (44.0%) (containing DST140 and DST98). All azole non-WT isolates carried the ERG11 mutations A395T/W and/or C461T/Y, and most carried the UPC2 mutation T503C/Y. These mutations were not identified in low and high trailing WT isolates. Azole non-WT and high trailing WT isolates exhibited the highest expression levels of ERG11 and MDR1, 3.91- and 2.30-fold, respectively (both overall p < 0.01). Conclusions: Azole resistance and trailing are phenotypically and genotypically different in C. tropicalis. Interference with azole binding and MDR1 up-regulation confer azole resistance and trailing, respectively.

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Trends in Antifungal Susceptibility amongCandida sp. Urinary Isolates from 1994 and 1998

Journal of Clinical Microbiology ◽

10.1128/jcm.38.2.870-871.2000 ◽

2000 ◽

Vol 38 (2) ◽

pp. 870-871 ◽

Cited By ~ 12

Author(s):

Joseph Baran ◽

Enid Klauber ◽

Jeffrey Barczak ◽

Kathleen Riederer ◽

Riad Khatib

Keyword(s):

Candida Albicans ◽

Amphotericin B ◽

Candida Tropicalis ◽

Candida Glabrata ◽

Antifungal Susceptibility ◽

Geometric Means ◽

Fluconazole Resistance ◽

Urinary Isolates

Antifungal susceptibilities were determined from 80 urinary isolates of Candida species collected in 1994 and 1998. Our findings demonstrate increasing geometric means of fluconazole MICs and fluconazole resistance in Candida albicans andCandida tropicalis (those for Candida glabratawere unchanged) within the 4-year span. Amphotericin B and voriconazole MICs remained constant.

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Acquired multi-azole resistance in Candida tropicalis during persistent urinary tract infection in a dog

Medical Mycology Case Reports ◽

10.1016/j.mmcr.2016.02.001 ◽

2016 ◽

Vol 11 ◽

pp. 9-12 ◽

Cited By ~ 7

Author(s):

Sergio Álvarez-Pérez ◽

Marta E. García ◽

María Teresa Cutuli ◽

María Luisa Fermín ◽

María Ángeles Daza ◽

...

Keyword(s):

Urinary Tract Infection ◽

Urinary Tract ◽

Tract Infection ◽

Candida Tropicalis ◽

Azole Resistance

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ERG11 Gene Mutations and MDR1 Upregulation Confer Pan-Azole Resistance in Candida tropicalis Causing Disseminated Candidiasis in an Acute Lymphoblastic Leukemia Patient on Posaconazole Prophylaxis

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02496-16 ◽

2017 ◽

Vol 61 (7) ◽

Cited By ~ 12

Author(s):

Liangshun You ◽

Wenbin Qian ◽

Qing Yang ◽

Liping Mao ◽

Li Zhu ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Candida Tropicalis ◽

Rare Case ◽

Lymphoblastic Leukemia ◽

Gene Mutations ◽

Efflux Pumps ◽

Resistance Mechanisms ◽

Azole Resistance ◽

Content Type ◽

Leukemia Patient

ABSTRACT In this study, we present a rare case of fatal breakthrough Candida tropicalis infection in a patient with acute lymphoblastic leukemia (ALL) while on posaconazole prophylaxis. Then, we explore the mechanisms underlying azole resistance by focusing on enhanced efflux pumps and changes in the azole target enzyme Erg11p, which was encoded by the ERG11 gene. Our study demonstrates that Y132C substitution of Erg11p combined with MDR1 overexpression may be the pan-azole resistance mechanisms in Candida tropicalis.

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