What do we know about the biology of the emerging fungal pathogen of humans Candida auris?

Ruiz, Gustavo Bravo; Lorenz, Alexander

doi:10.1016/j.micres.2020.126621

Cited by 53 publications

(68 citation statements)

References 144 publications

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“…While resistance to single agents has been reported in this species [4,5], resistance to multiple agents (multidrug resistance, MDR) has also been documented [6,7]. Candida auris, which is phylogenetically closely related to C. lusitaniae and is a recently emerging fungal pathogen, exhibits quite similar characteristics in terms of rapid drug resistance acquisition and multidrug resistance [8].…”

Section: Introductionmentioning

confidence: 99%

Participation of the ABC Transporter CDR1 in Azole Resistance of Candida lusitaniae

Borgeat

Brandalise

Grenouillet

et al. 2021

JoF

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Candida lusitaniae is an opportunistic pathogen in humans that causes infrequent but difficult-to-treat diseases. Antifungal drugs are used in the clinic to treat C. lusitaniae infections, however, this fungus can rapidly acquire antifungal resistance to all known antifungal drugs (multidrug resistance). C. lusitaniae acquires azole resistance by gain-of-function (GOF) mutations in the transcriptional regulator MRR1. MRR1 controls the expression of a major facilitator transporter (MFS7) that is important for fluconazole resistance. Here, we addressed the role of the ATP Binding Cassette (ABC) transporter CDR1 as additional mediator of azole resistance in C. lusitaniae. CDR1 expression in isolates with GOF MRR1 mutations was higher compared to wild types, which suggests that CDR1 is an additional (direct or indirect) target of MRR1. CDR1 deletion in the azole-resistant isolate P3 (V688G GOF) revealed that MICs of long-tailed azoles, itraconazole and posaconazole, were decreased compared to P3, which is consistent with the role of this ABC transporter in the efflux of these azoles. Fluconazole MIC was only decreased when CDR1 was deleted in the background of an mfs7Δ mutant from P3, which underpins the dominant role of MFS7 in the resistance of the short-tailed azole fluconazole. With R6G efflux readout as Cdr1 efflux capacity, our data showed that R6G efflux was increased in P3 compared to an azole-susceptible wild type parent, and diminished to background levels in mutant strains lacking CDR1. Milbemycin oxim A3, a known inhibitor of fungal ABC transporters, mimicked efflux phenotypes of cdr1Δ mutants. We therefore provided evidence that CDR1 is an additional mediator of azole resistance in C. lusitaniae, and that CDR1 regulation is dependent on MRR1 and associated GOF mutations.

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Section: Introductionmentioning

confidence: 99%

Participation of the ABC Transporter CDR1 in Azole Resistance of Candida lusitaniae

Borgeat

Brandalise

Grenouillet

et al. 2021

JoF

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“…Through stimuli external to the cell, the enzyme adenylate cyclase converts ATP to adenosine 3 ,5 -cyclic monophosphate (cAMP), an important secondary messenger that binds to the catalytic subunit of protein kinase A (PKA). This generates a conformational change that releases PKA catalytic subunits and activates transcription factors and other signalling pathways involved in cell wall integrity, stress response and virulence [58,60,61]. Thus, Pb18 yeasts treated or not with iDrk1 for 24 h were lysed, and the protein extract was used to quantify the PKA activity and cAMP dosage.…”

Section: Regulation Of Camp-pka and Glycogen Accumulation In P Brasiliensismentioning

confidence: 99%

The Role of Dimorphism Regulating Histidine Kinase (Drk1) in the Pathogenic Fungus Paracoccidioides brasiliensis Cell Wall

Navarro

Barros

Segura

et al. 2021

JoF

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Dimorphic fungi of the Paracoccidioides genus are the causative agents of paracoccidioidomycosis (PCM), an endemic disease in Latin America with a high incidence in Brazil. This pathogen presents as infective mycelium at 25 °C in the soil, reverting to its pathogenic form when inhaled by the mammalian host (37 °C). Among these dimorphic fungal species, dimorphism regulating histidine kinase (Drk1) plays an essential role in the morphological transition. These kinases are present in bacteria and fungi but absent in mammalian cells and are important virulence and cellular survival regulators. Hence, the purpose of this study was to investigate the role of PbDrk1 in the cell wall modulation of P. brasiliensis. We observed that PbDrk1 participates in fungal resistance to different cell wall-disturbing agents by reducing viability after treatment with iDrk1. To verify the role of PbDRK1 in cell wall morphogenesis, qPCR results showed that samples previously exposed to iDrk1 presented higher expression levels of several genes related to cell wall modulation. One of them was FKS1, a β-glucan synthase that showed a 3.6-fold increase. Furthermore, confocal microscopy analysis and flow cytometry showed higher β-glucan exposure on the cell surface of P. brasiliensis after incubation with iDrk1. Accordingly, through phagocytosis assays, a significantly higher phagocytic index was observed in yeasts treated with iDrk1 than the control group, demonstrating the role of PbDrk1 in cell wall modulation, which then becomes a relevant target to be investigated. In parallel, the immune response profile showed increased levels of proinflammatory cytokines. Finally, our data strongly suggest that PbDrk1 modulates cell wall component expression, among which we can identify β-glucan. Understanding this signalling pathway may be of great value for identifying targets of antifungal molecular activity since HKs are not present in mammals.

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“…Although Candida albicans has historically been the most prominent Candida species associated with both superficial and invasive fungal infections, worldwide incidence of nonalbicans Candida (NAC) species is increasing (1)(2)(3)(4)(5)(6)(7)(8)(9)(10). Of particular concern is Candida auris, which the CDC classifies as an urgent threat due to its relatively high frequency of resistance to multiple different classes of drugs including amphotericin B, echinocandins and azoles (reviewed in (11)). Since its recognition as a novel Candida species in 2009, C. auris, has been reported in at least 40 countries (12)(13)(14).…”

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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What do we know about the biology of the emerging fungal pathogen of humans Candida auris?

Cited by 53 publications

References 144 publications

Participation of the ABC Transporter CDR1 in Azole Resistance of Candida lusitaniae

Participation of the ABC Transporter CDR1 in Azole Resistance of Candida lusitaniae

The Role of Dimorphism Regulating Histidine Kinase (Drk1) in the Pathogenic Fungus Paracoccidioides brasiliensis Cell Wall

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

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