Pan-azole-resistant<i>Candida tropicalis</i>carrying homozygous<i>erg11</i>mutations at position K143R: a new emerging superbug?

Xisto, Mariana Ingrid Dutra da Silva; Caramalho, Rita; Rocha, Débora Afonso Silva; Ferreira‐Pereira, Antônio; Sartori, Bettina; Barreto‐Bergter, Eliana; Junqueira, Maria Luiza; Lass‐Flörl, Cornelia; Lackner, Michaela

doi:10.1093/jac/dkw558

Cited by 29 publications

(22 citation statements)

References 33 publications

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“…Studies have demonstrated that Erg11p amino acid substitutions in the 14α-sterol demethylase involved in the biosynthesis of sterol ergosterol results in decreased fluconazole susceptibility in C. tropicalis clinical isolates [ 9 , 20 , 21 ]. Jiang et al demonstrated that two mutations, Y132F and S154F, are responsible for azole resistance by inserting them into wild-type isolate [ 14 ].…”

Section: Discussionmentioning

confidence: 99%

MDR1 overexpression combined with ERG11 mutations induce high-level fluconazole resistance in Candida tropicalis clinical isolates

et al. 2018

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BackgroundMarked increases in fluconazole resistance in Candida tropicalis have been recently reported. In this study, the molecular mechanisms behind fluconazole resistance were investigated.MethodsTwenty-two C. tropicalis clinical isolates, including 12 fluconazole-resistant isolates and 10 fluconazole-susceptible isolates, were collected from a tertiary care teaching hospital in Beijing between 2013 and 2017. Antifungal susceptibility testing, multilocus sequence typing, ERG11 amplification and sequencing, quantitative real-time reverse transcription-polymerase chain reaction (ERG11, UPC2, MDR1, and CDR1), and clinical data collection were performed for all C. tropicalis isolates.ResultsMultilocus sequence typing revealed that the 10 fluconazole-susceptible isolates and 12 fluconazole-resistant isolates were divided into nine and seven diploid sequence types, respectively. Of the 12 patients with fluconazole-resistant isolates, six had been previously exposed to azole and four had a fatal outcome. Y132F and S154F amino acid substitutions in Erg11p were found in all fluconazole-resistant isolates except one. MDR1 gene overexpression was identified in fluconazole-resistant isolates. In particular, seven high-level fluconazole resistant isolates (minimum inhibitory concentration ≥ 128 mg/L) and three pan-azole resistant isolates were identified. CDR1, ERG11, and UPC2 gene expression levels in fluconazole-resistant isolates were not significantly different from the control isolates (P = 0.262, P = 0.598, P = 0.114, respectively).ConclusionsThis study provides evidence that the combination of MDR1 gene overexpression and ERG11 missense mutations is responsible for high-level fluconazole resistance and pan-azole resistance in C. tropicalis clinical isolates. To the best of our knowledge, this is the first study investigating the relationship between MDR1 gene overexpression and increased fluconazole resistance.

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Section: Discussionmentioning

confidence: 99%

MDR1 overexpression combined with ERG11 mutations induce high-level fluconazole resistance in Candida tropicalis clinical isolates

et al. 2018

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“…These expression studies were later verified through direct expression in C. albicans ( 11 ). The equivalent Y132F and/or K143R substitutions were also associated with azole resistance in Candida tropicalis ( 12 – 14 ), Candida parapsilosis ( 15 , 16 ), and Candida orthopsilosis ( 17 ). Residues Tyr132 and Lys143 lie within the substrate binding pocket of the Erg11 protein (lanosterol 14α-demethylase) and have been shown in S. cerevisiae to directly interact with and stabilize the binding of fluconazole ( 18 ).…”

Section: Textmentioning

confidence: 99%

Limited ERG11 Mutations Identified in Isolates of Candida auris Directly Contribute to Reduced Azole Susceptibility

Healey

Kordalewska

Ortigosa

et al. 2018

Antimicrob Agents Chemother

143

132

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Multiple Erg11 amino acid substitutions were identified in clinical isolates of Candida auris originating from India and Colombia. Elevated azole MICs were detected in Saccharomyces cerevisiae upon heterologous expression of C. auris ERG11 alleles that encoded for Y132F or K143R substitutions; however, expression of alleles encoding I466M, Y501H, or other clade-defined amino acid differences yielded susceptible MICs.

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“…Fungi contain multiple mechanisms that regulate mutagenesis, including several highlyconserved DNA repair systems, such as double-strand break repair (DSBR), base-excision repair (BER), nucleotide-excision repair (NER), post-replication repair (PRR), and mismatch repair (MMR). DNA polymerases, including several error-prone polymerases, also impinge on mutation rates [90][91][92] . Defects or programmed changes (e.g.…”

Section: Micmentioning

confidence: 99%

Fungal resistance to echinocandins and the MDR phenomenon in Candida glabrata

Healey¹,

Perlin²

2018

Preprint

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Candida glabrata has thoroughly adapted to successfully colonize human mucosal membranes and survive in vivo pressures prior to and during antifungal treatment. Out of all the medically relevant Candida species, C. glabrata has emerged as a leading cause of azole, echinocandin, and multidrug (MDR: azole + echinocandin) adaptive resistance. Neither mechanism of resistance is intrinsic to C. glabrata, since stable genetic resistance depends on mutation of drug target genes, FKS1 and FKS2 (echinocandin resistance), and a transcription factor, PDR1, which controls expression of major drug transporters, such as CDR1 (azole resistance). However, another hallmark of C. glabrata is the ability to withstand drug pressure both in vitro and in vivo prior to stable ‘genetic escape’. Additionally, these resistance events can arise within individual patients, which underscores the importance of understanding how this fungus is adapting to its environment and to drug exposure in vivo. Here, we explore the evolution of echinocandin resistance as a multistep model that includes general cell stress, drug adaptation (tolerance), and genetic escape. The extensive genetic diversity reported in C. glabrata will be highlighted.

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Pan-azole-resistantCandida tropicaliscarrying homozygouserg11mutations at position K143R: a new emerging superbug?

Cited by 29 publications

References 33 publications

MDR1 overexpression combined with ERG11 mutations induce high-level fluconazole resistance in Candida tropicalis clinical isolates

MDR1 overexpression combined with ERG11 mutations induce high-level fluconazole resistance in Candida tropicalis clinical isolates

Limited ERG11 Mutations Identified in Isolates of Candida auris Directly Contribute to Reduced Azole Susceptibility

Fungal resistance to echinocandins and the MDR phenomenon in Candida glabrata

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