Abrogation of Triazole Resistance upon Deletion of
            <i>CDR1</i>
            in a Clinical Isolate of
            <i>Candida auris</i>

Rybak, Jeffrey M.; Doorley, Laura A.; Nishimoto, Andrew T.; Barker, Katherine S.; Palmer, Glen E.; Rogers, P. David

doi:10.1128/aac.00057-19

Cited by 105 publications

(165 citation statements)

References 15 publications

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“…MDR1 and MDR2 , on the other hand, were not having consistent expression level in all the isolates of C. auris . It has already been mentioned (19) that CDR1 is relatively more expressed as compared to MDR1 . Additionally, both CDR2 and MDR2 expression were not raised in any of the isolates.…”

Section: Resultsmentioning

confidence: 90%

“…Candida auris is an emerging MDR pathogen with higher MIC values against commonly used antifungal drugs when compared to other Candida species and the molecular basis of its MDR still remains unclear. Few studies have come up recently that has provided insight into transcriptomic assembly of C. auris and revealed the possible mechanism of drug resistance among these isolates (32, 19). For understanding the molecular basis of farnesol on C. auris drug efflux pumps and biofilm formation, we studied gene expression in C. auris.…”

Section: Resultsmentioning

confidence: 99%

“…The mRNA expression level for CDR1, CDR2, SNQ2, HYR3, IFF4, PGA7, PGA26, PGA52, MDR1, MDR2 and ACT1 (housekeeping gene) were measured using RT-qPCR. The method was taken from previous study described elsewhere with minor adjustments (19). Briefly, C. auris isolates (MRL 6057, MRL 2397, MRL 5762 and MRL 5765) were incubated overnight at 37 °C SDB medium.…”

Section: Methodsmentioning

confidence: 99%

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Abrogation of pathogenic attributes in drug resistantCandida aurisstrains by farnesol

Srivastava

Ahmad

2019

Preprint

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AbstractCandida auris, a decade old Candida species, has been identified globally as a significant nosocomial multidrug resistant (MDR) pathogen responsible for causing invasive outbreaks. Biofilms and overexpression of efflux pumps such as Major Facilitator Superfamily and ATP Binding Cassette are known to cause multidrug resistance in Candida species, including C. auris. Therefore, targeting these factors may prove an effective approach to combat MDR in C. auris. In this study, 25 clinical isolates of C. auris from different hospitals of South Africa were used. All the isolates were found capable enough to form biofilms on 96-well microtiter plate that was further confirmed by MTT reduction assay. In addition, these strains have active drug efflux mechanism which was supported by rhodamine-6-G extracellular efflux and intracellular accumulation assays. Antifungal susceptibility profile of all the isolates against commonly used drugs was determined following CLSI recommended guidelines. We further studied the role of farnesol, an endogenous quorum sensing molecule, in modulating development of biofilms and drug efflux in C. auris. The MIC for planktonic cells ranged from 62.5-125 mM and for sessile cells was 125 mM (0 h and 4 h biofilm) and 500 mM (12 h and 24 h biofilm). Farnesol inhibited biofilm formation, blocked efflux pumps and downregulated biofilm- and efflux pump-associated genes. Modulation of C. auris biofilm formation and efflux pump activity by farnesol represent a promising approach for controlling life threatening infections caused by this pathogen.

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Section: Resultsmentioning

confidence: 90%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Abrogation of pathogenic attributes in drug resistantCandida aurisstrains by farnesol

Srivastava

Ahmad

2019

Preprint

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“…Fluconazole MIC were then determined for the parental AR0387 and each of the five fluconazole-evolved strains by broth microdilution in accordance with Clinical Laboratory Standards Institute methodology with minor modifications as previously described. (20) AR0387 exhibited a fluconazole MIC of 1mg/L, while the five fluconazole-evolved strains were found to have MIC ranging from 8 to 64mg/L ( Figure 2 ). Each of the second-generation evolved strains, FLU-A2 and FLU-C2, exhibited a further 2 to 4-fold increase in fluconazole MIC relative to their respective first-generation strains.…”

Section: Resultsmentioning

confidence: 99%

“…(17-19) Furthermore, the increased expression of the C. auris ABC-type efflux pump-encoding gene, CDR1 , has previously been shown to substantially contribute to clinical triazole resistance. (20, 21) At present however, the genetic determinants underpinning the increased expression of efflux pump-encoding genes in C. auris remain unidentified.…”

Section: Introductionmentioning

confidence: 99%

Mutations inTAC1B: a novel genetic determinant of clinical fluconazole resistance inC. auris

Rybak

Muñoz

Barker

et al. 2020

Preprint

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Candida auris has emerged as a multidrug-resistant pathogen of great clinical concern. Approximately 90% of clinical C. auris isolates are resistant to fluconazole, the most commonly prescribed antifungal agent, yet it remains unknown what mechanisms underpin this fluconazole resistance. To identify novel mechanisms contributing to fluconazole resistance in C. auris, the fluconazole-susceptible C. auris clinical isolate AR0387 was passaged in media supplemented with fluconazole to generate derivative strains which had acquired increased fluconazole resistance in vitro. Comparative analysis of comprehensive sterol profiles, [3H]-fluconazole uptake, sequencing of C. auris genes homologous to genes known to contribute to fluconazole resistance in other species of Candida, and the relative expression of C. auris ERG11, CDR1, and MDR1 were performed. All fluconazole-evolved derivative strains were found to have acquired mutations in the zinc-cluster transcription factor-encoding gene, TAC1B, and a corresponding increase in CDR1 expression relative to the parental clinical isolate, AR0387. Mutations in TAC1B were also identified in a set of 304 globally distributed C. auris clinical isolates representing each of the four major clades. Introduction of the most common mutation found among fluconazole-resistant clinical isolates of C. auris into the fluconazole-susceptible isolate AR0387, was confirmed to increase fluconazole resistance by 8-fold, and the correction of the same mutation in a fluconazole-resistant isolate, AR0390, decreased fluconazole MIC by 16-fold. Taken together, these data demonstrate that C. auris can rapidly acquire resistance to fluconazole in-vitro, and that mutations in TAC1B significantly contribute to clinical fluconazole resistance.IMPORTANCECandida auris is an emerging multidrug-resistant pathogen of global concern, known to be responsible for outbreaks on six continents and commonly resistant to antifungals. While the vast majority of clinical C. auris isolates are highly resistant to fluconazole, an essential part of the available antifungal arsenal, very little is known about the mechanisms contributing to resistance. In this work, we show that mutations in the transcription factor TAC1B significantly contribute to clinical fluconazole resistance. These studies demonstrate that mutations in TAC1B can arise rapidly in vitro upon exposure to fluconazole, and that a multitude of resistance-associated TAC1B mutations are present among the majority of fluconazole-resistant C. auris isolates from a global collection and appear specific to a subset of lineages or clades. Thus, identification of this novel genetic determinant of resistance significantly adds to the understanding of clinical antifungal resistance in C. auris.

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Bioinformatic Identification of ABC Transporters in Candida auris

Banerjee

Vishwakarma

Meena

et al. 2022

Methods in Molecular Biology

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Abrogation of Triazole Resistance upon Deletion of CDR1 in a Clinical Isolate of Candida auris

Cited by 105 publications

References 15 publications

Abrogation of pathogenic attributes in drug resistantCandida aurisstrains by farnesol

Abrogation of pathogenic attributes in drug resistantCandida aurisstrains by farnesol

Mutations inTAC1B: a novel genetic determinant of clinical fluconazole resistance inC. auris

Bioinformatic Identification of ABC Transporters in Candida auris

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