First detection of mutated ERG11 gene in vulvovaginal Candida albicans isolates at Ouagadougou/Burkina Faso

Dovo, Essi Etonam; Zohoncon, Théodora Mahoukèdè; Tovo, S; Soubeïga, Serge Théophile; Kiendrebeogo, Isabelle Touwendpoulimdé; Yonli, Albert Théophane; Ouedraogo, Rogomenona Alice; Dabiré, Amana Mètuor; Djigma, Florencia Wendkuuni; Nadembèga, Christelle; Belemgnegre, Marius; Ouédraogo, Paul; Obiri‐Yeboah, Dorcas; Simporé, Jacques

doi:10.1186/s12879-022-07619-5

Cited by 5 publications

(3 citation statements)

References 37 publications

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“…Analysis of individual genes showed that 12 ergosterol metabolism genes were significantly up-regulated in Esc7 in ethanol compared to SC5314 in ethanol ( figure 2B) . Importantly, one of these 12 genes was ERG11 which is one of the rate-limiting steps of ergosterol biosynthesis and the target of azole antifungals [18,19]. Previous work with Saccharomyces cerevisiae showed that ethanol impacts ergosterol production and that increased ergosterol production was correlated with increased ethanol tolerance [20–23], suggesting that the observed up-regulation of ERG genes contributes to ethanol tolerance of Esc7.…”

Section: Resultsmentioning

confidence: 99%

Selection of Ethanol Tolerant Strains ofCandida albicansby Repeated Ethanol Exposure Results in Strains with Reduced Susceptibility to Fluconazole

Day,

Kumamoto

2023

Preprint

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Candida albicans is a commensal yeast that has important impacts on host metabolism and immune function, and can establish life-threatening infections in immunocompromised individuals. Previously, C. albicans colonization has been shown to contribute to the progression and severity of alcoholic liver disease. However, relatively little is known about how C. albicans responds to changing environmental conditions in the GI tract of individuals with alcohol use disorder, namely repeated exposure to ethanol. In this study, we repeatedly exposed C. albicans to high concentrations (10% vol/vol) of ethanol—a concentration that can be observed in the upper GI tract of humans following consumption of alcohol. Following this repeated exposure protocol, ethanol small colony (Esc) variants of C. albicans isolated from these populations exhibited increased ethanol tolerance, altered transcriptional responses to ethanol, and cross-resistance/tolerance to the frontline antifungal fluconazole. These Esc strains exhibited chromosomal copy number variations and carried polymorphisms in genes previously associated with the acquisition of fluconazole resistance during human infection. This study identifies a selective pressure that can result in evolution of fluconazole tolerance and resistance without previous exposure to the drug. Author Summary: Previous work has shown that Candida albicans, a common fungal component of the gastrointestinal (GI) microbiome, is found in high abundance in the alcoholic GI tract. However, it was unknown how repeated ethanol exposure, similar to what C. albicans would be exposed to in the upper GI tract of individuals with alcohol use disorder, would affect the yeast. In this work, we show that repeated ethanol exposure selects for C. albicans strains with altered transcriptional responses to ethanol, increased ethanol tolerance, and cross-resistance/tolerance to the common frontline antifungal fluconazole. This work shows that ethanol exposure can promote evolution of C. albicans to antifungal resistance without previous exposure to the antifungal drug. These findings could be relevant to C. albicans in the upper GI tract in individuals with alcohol use disorder and further studies could reveal optimized antifungal regimens for C. albicans infections in these patients.

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Section: Resultsmentioning

confidence: 99%

Selection of Ethanol Tolerant Strains ofCandida albicansby Repeated Ethanol Exposure Results in Strains with Reduced Susceptibility to Fluconazole

Day,

Kumamoto

2023

Preprint

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“…The azole antifungals target lanosterol demethylase Erg11p, is a key enzyme in ergosterol biosynthesis pathway ( 37 ). It has been reported that the upregulation of ERG11 has also been observed in several azole-resistant isolates.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of virulence factors and azole resistance mechanisms of Candida tropicalis isolates from head and neck cancer patients with OPC

Jahanshiri¹,

Manifar²,

Hatami³

2023

IJM

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Background and Objectives: Candida tropicalis is one of the major non-albicans species causing nosocomial infection. There is limited data about mechanisms of azole-resistance and virulence factors of Candida tropicalis. This study was designed to investigate molecular mechanism of azole -resistance and major virulence factors of C. tropicalis isolated from oropharyngeal candidiasis in head and neck cancer patients. Materials and Methods: After collecting 38 C. tropicalis clinical isolates, antifungal susceptibility pattern and the expression levels of ERG11, CDR1, CDR2 and MDR1 were evaluated. Moreover, proteinase and phospholipase activity and biofilm formation of the isolates were investigated as virulence factors. Results: We detected fluconazole resistance in 7 C. tropicalis isolates. The expression levels of CDR1, ERG11 and MDR1 were increased respectively. Protease activity and biofilm formation were seen in all isolates. Five isolates did not exhibit phospholipase activity. Conclusion: Taken together, the overexpressions of ERG11, CDR1 and MDR1 genes were found in fluconazole resistant C. tropicalis, isolated from oropharyngeal candidiasis patients. Also, voriconazole was an effective antifungal against C. tropicalis isolates. The observed high protease enzyme activity and biofilm formation suggested strong pathogenicity of these isolates.

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“…In recent years, however, the formation of C. albicans biofilms has made the treatment of fungi ineffective, resulting in reduced of C. albicans susceptibility to fluconazole. This increase in drug resistance has hampered the penetration and absorption of azole drugs and reduced the number of antifungal drug targets [12][13][14][15]. In addition, mutations and the overexpression of ERG11 weaken the binding of the drug to the target enzyme.…”

Section: Introductionmentioning

confidence: 99%

Mechanism and bioinformatics analysis of the effect of berberine-enhanced fluconazole against drug-resistant Candida albicans

Wu,

Jia,

et al. 2024

BMC Microbiol

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Biofilms produced by Candida albicans present a challenge in treatment with antifungal drug. Enhancing the sensitivity to fluconazole (FLC) is a reasonable method for treating FLC-resistant species. Moreover, several lines of evidence have demonstrated that berberine (BBR) can have antimicrobial effects. The aim of this study was to clarify the underlying mechanism of these effects. We conducted a comparative study of the inhibition of FLC-resistant strain growth by FLC treatment alone, BBR treatment alone, and the synergistic effect of combined FLC and BBR treatment. Twenty-four isolated strains showed distinct biofilm formation capabilities. The antifungal effect of combined FLC and BBR treatment in terms of the growth and biofilm formation of Candida albicans species was determined via checkerboard, time-kill, and fluorescence microscopy assays. The synergistic effect of BBR and FLC downregulated the expression of the efflux pump genes CDR1 and MDR, the hyphal gene HWP1, and the adhesion gene ALS3; however, the gene expression of the transcriptional repressor TUP1 was upregulated following treatment with this drug combination. Furthermore, the addition of BBR led to a marked reduction in cell surface hydrophobicity. To identify resistance-related genes and virulence factors through genome-wide sequencing analysis, we investigated the inhibition of related resistance gene expression by the combination of BBR and FLC, as well as the associated signaling pathways and metabolic pathways. The KEGG metabolic map showed that the metabolic genes in this strain are mainly involved in amino acid and carbon metabolism. The metabolic pathway map showed that several ergosterol (ERG) genes were involved in the synthesis of cell membrane sterols, which may be related to drug resistance. In this study, BBR + FLC combination treatment upregulated the expression of the ERG1, ERG3, ERG4, ERG5, ERG24, and ERG25 genes and downregulated the expression of the ERG6 and ERG9 genes compared with fluconazole treatment alone (p < 0.05).

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First detection of mutated ERG11 gene in vulvovaginal Candida albicans isolates at Ouagadougou/Burkina Faso

Cited by 5 publications

References 37 publications

Selection of Ethanol Tolerant Strains ofCandida albicansby Repeated Ethanol Exposure Results in Strains with Reduced Susceptibility to Fluconazole

Selection of Ethanol Tolerant Strains ofCandida albicansby Repeated Ethanol Exposure Results in Strains with Reduced Susceptibility to Fluconazole

Evaluation of virulence factors and azole resistance mechanisms of Candida tropicalis isolates from head and neck cancer patients with OPC

Mechanism and bioinformatics analysis of the effect of berberine-enhanced fluconazole against drug-resistant Candida albicans

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