Aneuploidy Mediates Rapid Adaptation to a Subinhibitory Amount of Fluconazole in Candida albicans

Sun, Liu-Liu; Li, Hao; Yan, Tianhua; Fang, Ting; Wu, Hao; Cao, Yongbing; Lü, Hui; Jiang, Yuanying; Yang, Feng

doi:10.1128/spectrum.03016-22

“…Our study illustrates that brief exposure to mild ER stress is adequate to trigger aneuploidy in C. neoformans, mirroring our previous ndings in C. albicans [15]. Additionally, besides ER stress, shortterm exposure to sub-inhibitory concentrations of FLC also prompts aneuploidy in C. neoformans [9] and C. albicans [26][27][28]. Thus, we propose that the genome plasticity of fungal pathogens can be readily and swiftly induced by mild stresses.…”

Section: Discussionsupporting

confidence: 85%

Unveiling Genome Plasticity as a Mechanism of Non-Antifungal-Induced Antifungal Resistance in Cryptococcus neoformans

Zheng,

Xu,

Wang

et al. 2024

Preprint

0

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Cryptococcus neoformans, designated as a "critical priority" pathogen by the World Health Organization, poses significant therapeutic challenges with only three drug classes currently available for cryptococcosis treatment. The emergence of antifungal resistance, compounded by cross-resistance, further limits therapeutic efficacy. Aneuploidy, known for its potential to induce diverse traits, including antifungal resistance, remains poorly documented in C. neoformans. Utilizing tunicamycin, a well-established ER stress inducer, we investigated its impact on aneuploidy formation in C. neoformans. Our findings reveal that both mild and severe ER stress induced by tunicamycin result in the formation of aneuploidy in C. neoformans. These aneuploid strains exhibit diverse karyotypes, with select karyotypes conferring resistance or cross-resistance to fluconazole and 5-flucytosine. Additionally, these aneuploid strains display instability, spontaneously losing extra chromosomes in the absence of stress. Transcriptome analysis unveiled simultaneous upregulation of multiple drug resistance-associated genes in aneuploid strains, highlighting the genome plasticity of C. neoformans as a major mechanism contributing to non-antifungal-induced antifungal resistance.

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“…Aneuploidies found in Esc8 included a monosomy of Chr5, and trisomies of Chr6, Chr7, and ChrR. ChrR trisomy has been found in fluconazole tolerant strains and shown to confer increased fluconazole tolerance [ 62 – 64 ]. Aneuploidies may contribute to the reduced fluconazole susceptibility of Esc8.…”

Section: Discussionmentioning

confidence: 99%

“…Some of the chromosome aneuploidies observed in Esc7 and Esc8 have been previously observed in strains with altered susceptibility to the frontline antifungal fluconazole. Aneuploidies of chromosome 3, 5, 6, 7, and R have been implicated in azole resistance and tolerance [59][60][61][62][63][64]. Further, the ergosterol pathway, more specifically ERG11, is the target of azole class antifungals and increased expression of ERG11 and CDR1 confers fluconazole resistance [42,[65][66][67].…”

Section: Esc Strains Exhibit Reduced Susceptibility To Fluconazolementioning

confidence: 99%

Selection of ethanol tolerant strains of Candida albicans by repeated ethanol exposure results in strains with reduced susceptibility to fluconazole

Day,

Kumamoto

2024

PLoS ONE

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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.

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“…Some of the chromosome aneuploidies observed in Esc7 and Esc8 have been previously observed in strains with altered susceptibility to the frontline antifungal fluconazole. Aneuploidies of chromosome 3, 5, 6, 7, and R have been implicated in azole resistance and tolerance [53][54][55][56][57][58].…”

Section: Esc Strains Exhibit Reduced Susceptibility To Fluconazolementioning

confidence: 99%

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

Day,

Kumamoto

2023

Preprint

0

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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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Aneuploidy Mediates Rapid Adaptation to a Subinhibitory Amount of Fluconazole in Candida albicans

Abstract: Genome instability is a hallmark of C. albicans . Aneuploidy usually causes fitness loss in the absence of stress but confers better fitness under particular stress conditions.

Cited by 14 publications

References 40 publications

Unveiling Genome Plasticity as a Mechanism of Non-Antifungal-Induced Antifungal Resistance in Cryptococcus neoformans

Unveiling Genome Plasticity as a Mechanism of Non-Antifungal-Induced Antifungal Resistance in Cryptococcus neoformans

Selection of ethanol tolerant strains of Candida albicans by 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

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