Delineation of the Direct Contribution of Candida auris
            <i>ERG11</i>
            Mutations to Clinical Triazole Resistance

Rybak, Jeffrey M.; Sharma, Cheshta; Doorley, Laura A.; Barker, Katherine S.; Palmer, Glen E.; Rogers, P. David

doi:10.1128/spectrum.01585-21

Cited by 37 publications

(44 citation statements)

References 20 publications

(38 reference statements)

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“…In C. auris isolates, fluconazole resistance has been correlated with three amino acid substitutions in ERG11 : V125A/F126L, Y132F, and K143R ( 4 ). These mutations have been shown to increase fluconazole MICs by ~16-fold ( 10 ); however, mutations in ERG11 alone cannot explain the very high levels of resistance (MICs >256μg/mL fluconazole) observed in many C. auris isolates. Activating mutations in the transcriptional regulator of drug efflux pumps, TAC1B , have also been shown to be important for high levels of fluconazole resistance ( 11 ), and deletion of TAC1B abrogates resistance ( 12 ).…”

Section: Introductionmentioning

confidence: 99%

Genomic Diversity across Candida auris Clinical Isolates Shapes Rapid Development of Antifungal Resistance In Vitro and In Vivo

Burrack

Todd

Soisangwan

et al. 2022

mBio

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Section: Introductionmentioning

confidence: 99%

Genomic Diversity across Candida auris Clinical Isolates Shapes Rapid Development of Antifungal Resistance In Vitro and In Vivo

Burrack

Todd

Soisangwan

et al. 2022

mBio

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“…Therefore, the binding affinity of fluconazole to its target is reduced. The isolate with these mutations exhibited a 16-fold increase in fluconazole minimum inhibitory concentration (MIC) [ 8 ]. Missense mutations and silent point mutations in ERG3 are thought to be responsible for the mis-synthesized sterols and high levels of drug resistance [ 9 ].…”

Section: Antifungal Resistances Mediated By Genetic Mutationsmentioning

confidence: 99%

Genomic Variation-Mediating Fluconazole Resistance in Yeast

Wang

Cai

et al. 2022

Biomolecules

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Fungal infections pose a serious and growing threat to public health. These infections can be treated with antifungal drugs by killing hazardous fungi in the body. However, the resistance can develop over time when fungi are exposed to antifungal drugs by generating genomic variations, including mutation, aneuploidy, and loss of heterozygosity. The variations could reduce the binding affinity of a drug to its target or block the pathway through which drugs exert their activity. Here, we review genomic variation-mediating fluconazole resistance in the yeast Candida, with the hope of highlighting the functional consequences of genomic variations for the antifungal resistance.

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“…The resistance to azoles in C. auris is multifactorial; it has been shown that certain mutations in ERG11 (15,(23)(24)(25)(26)(27)(28)(29)(30)(31) and overproduction of Cdr1p (32)(33)(34)(35)(36) contribute to resistance to fluconazole (FLZ). In multiple Candida species, the transcriptional regulator Mrr1 also plays a role in FLZ resistance (37)(38)(39)(40)(41)(42)(43)(44)(45), and Mayr and colleagues (46) found three C. auris homologs of the transcriptional regulator Mrr1, and showed that one of them, MRR1a, modestly affected fluconazole resistance.…”

Section: Introductionmentioning

confidence: 99%

Transcriptional response of Candida auris to the Mrr1 inducers methylglyoxal and benomyl

Biermann

Hogan

2022

Preprint

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Candida auris is an urgent threat to human health due to its rapid spread in healthcare settings and its repeated development of multidrug resistance. Diseases that put individuals at a higher risk for C. auris infection, such as diabetes, kidney failure, or immunocompromising conditions, are associated with elevated levels of methylglyoxal (MG), a reactive dicarbonyl compound derived from several metabolic processes. In other Candida species, expression of MG reductase enzymes that catabolize and detoxify MG are controlled by Mrr1, a multidrug resistance-associated transcription factor, and MG induces Mrr1 activity. Here, we used transcriptomics and genetic assays to determine that C. auris MRR1a contributes to MG resistance, and that the main Mrr1a targets are an MG reductase and MDR1, which encodes an drug efflux protein. The C. auris Mrr1a regulon is smaller than Mrr1 regulons described in other species. In addition to MG, benomyl (BEN), a known Mrr1 stimulus, induces C. auris Mrr1 activity, and characterization of the MRR1a-dependent and independent transcriptional responses revealed substantial overlap in genes that were differentially expressed in response to each compound. Additionally, we found that an MRR1 allele specific to one C. auris phylogenetic clade, clade III, encodes a hyperactive Mrr1 variant, and this activity correlated with higher MG resistance. C. auris MRR1a alleles were functional in Candida lusitaniae and were inducible by BEN, but not by MG, suggesting that the two Mrr1 inducers act via different mechanisms. Together, the data presented in this work contribute to the understanding Mrr1 activity and MG resistance in C. auris.ImportanceCandida auris is a fungal pathogen that has spread since its identification in 2009 and is of concern due to its high incidence of resistance against multiple classes of antifungal drugs. In other Candida species, the transcription factor Mrr1 plays a major role in resistance against azole antifungals and other toxins. More recently, Mrr1 has been recognized to contribute to resistance to methylglyoxal (MG), a toxic metabolic byproduct. Here, we show that C. auris MRR1a, the closest ortholog to MRR1 in other species, contributes to resistance to MG, and that Mrr1a strongly co-regulates expression of MGD1, encoding a methylglyoxal reductase enzyme and MDR1, encoding an efflux protein involved in resistance to azole drugs, antimicrobial peptides and bacterial products. We found that one major clade of C. auris has a constitutively active Mrr1 despite high azole resistance due to other mutations, and that this high Mrr1a activity correlates with higher MG resistance. Finally, we gain insights into the activities of MG and another Mrr1 inducer, benomyl, to better understand C. auris regulation of phenotypes relevant in vivo.

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Delineation of the Direct Contribution of Candida auris ERG11 Mutations to Clinical Triazole Resistance

Abstract: Candida auris is an emerging multidrug-resistant and health care-associated pathogen of urgent clinical concern. The triazoles are the most widely prescribed antifungal agents worldwide and are commonly utilized for the treatment of invasive Candida infections.

Cited by 37 publications

References 20 publications

Genomic Diversity across Candida auris Clinical Isolates Shapes Rapid Development of Antifungal Resistance In Vitro and In Vivo

Genomic Diversity across Candida auris Clinical Isolates Shapes Rapid Development of Antifungal Resistance In Vitro and In Vivo

Genomic Variation-Mediating Fluconazole Resistance in Yeast

Transcriptional response of Candida auris to the Mrr1 inducers methylglyoxal and benomyl

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