Dynamics of in vitro development of azole resistance in Candida tropicalis

Paul, Saikat; Sharma, Deepshikha; Chakrabarti, Arunaloke; Rudramurthy, Shivaprakash M; Ghosh, Anup

doi:10.1016/j.jgar.2020.04.018

Cited by 22 publications

(22 citation statements)

References 37 publications

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“…Our results confirmed that neither ERG11 missense mutation nor overexpression was associated with azole resistance. In accordance with this finding, ERG11 nonsynonymous mutations were not identified after an in vitro induction of fluconazole resistance [12]. On the other hand, several ERG11 missense mutations have recently been confirmed in C. tropicalis to be associated with azole resistance, such as V125A, Y257H and G464S in China [2] and Y132F and S154F in Thailand [1].…”

Section: Discussionsupporting

confidence: 52%

“…Our results confirmed the significant overexpression of efflux transporters (CDR2 and CDR3), transcription factors (TAC1 and UPC2) and the HMG gene in resistant isolates. The role of CDR2, CDR3, TAC1 and UPC2 overexpression in C. tropicalis in inducing azole resistance has been confirmed by an in vitro induction study of fluconazole resistance [12], and UPC2 overexpression has also been observed in clinical azole-resistant C. tropicalis isolates [13]. Furthermore, CDR2 overexpression has recently been identified in azole-resistant clinical Candida glabrata and C. albicans isolates [14].…”

Section: Discussionmentioning

confidence: 79%

See 1 more Smart Citation

Azole and echinocandin resistance mechanisms and genotyping of Candida tropicalis in Japan: cross-boundary dissemination and animal–human transmission of C. tropicalis infection

Khalifa

Watanabe

Kamei

2022

Clinical Microbiology and Infection

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Section: Discussionsupporting

confidence: 52%

Section: Discussionmentioning

confidence: 79%

Azole and echinocandin resistance mechanisms and genotyping of Candida tropicalis in Japan: cross-boundary dissemination and animal–human transmission of C. tropicalis infection

Khalifa

Watanabe

Kamei

2022

Clinical Microbiology and Infection

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“…In C. albicans , TAC1 regulates the ABC transporter genes CDR1 and CDR2 , while MRR1 regulates the major facilitator MDR1 [ 10 , 18 , 27 , 28 ]. In the past few years, TAC1 and MRR1 homologs have been described in several other fungal pathogens including Candida parapsilosis , Candida tropicalis and C. auris [ 29 , 30 , 31 ]. A TAC1 homolog exists in C. lusitaniae (CLUG_02369) with about 55% similarity to the C. albicans TAC1 .…”

Section: Discussionmentioning

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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“…The downregulation of ALS3, which is associated with adhesion in C. albicans, supported our results of in vitro biofilm eradication. On the contrary, WMR/FLC treatment increased expression levels of ERG11, indicating a possible negative interaction of the combination targeting enzyme CYP51 encoded by ERG11 and leading to azole resistance, but it needs to be pointed out that ERG11 is only one of the genes of the ergosterol biosynthesis pathway (ERG1, ERG2, ERG3, and ERG11) [38]. F. oxysporum VeA and VelB genes, encoding for key regulators of the velvet complex, influence the growth and development of fungal hyphae, conidiation, secondary metabolism, and pathogenicity in both plants and mammals [39].…”

Section: Discussionmentioning

confidence: 99%

Competitiveness during Dual-Species Biofilm Formation of Fusarium oxysporum and Candida albicans and a Novel Treatment Strategy

et al. 2022

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During an infection, a single or multispecies biofilm can develop. Infections caused by non-dermatophyte molds, such as Fusarium spp. and yeasts, such as Candida spp., are particularly difficult to treat due to the formation of a mixed biofilm of the two species. Fusarium oxysporum is responsible for approximately 20% of human fusariosis, while Candida albicans is responsible for superficial mucosal and dermal infections and for disseminated bloodstream infections with a mortality rate above 40%. This study aims to investigate the interactions between C. albicans and F. oxysporum dual-species biofilm, considering variable formation conditions. Further, the ability of the WMR peptide, a modified version of myxinidin, to eradicate the mixed biofilm when used alone or in combination with fluconazole (FLC) was tested, and the efficacy of the combination of WMR and FLC at low doses was assessed, as well as its effect on the expression of some biofilm-related adhesin and hyphal regulatory genes. Finally, in order to confirm our findings in vivo and explore the synergistic effect of the two drugs, we utilized the Galleria mellonella infection model. We concluded that C. albicans negatively affects F. oxysporum growth in mixed biofilms. Combinatorial treatment by WMR and FLC significantly reduced the biomass and viability of both species in mature mixed biofilms, and these effects coincided with the reduced expression of biofilm-related genes in both fungi. Our results were confirmed in vivo since the synergistic antifungal activity of WMR and FLC increased the survival of infected larvae and reduced tissue invasion. These findings highlight the importance of drug combinations as an alternative treatment for C. albicans and F. oxysporum mixed biofilms.

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Dynamics of in vitro development of azole resistance in Candida tropicalis

Cited by 22 publications

References 37 publications

Azole and echinocandin resistance mechanisms and genotyping of Candida tropicalis in Japan: cross-boundary dissemination and animal–human transmission of C. tropicalis infection

Azole and echinocandin resistance mechanisms and genotyping of Candida tropicalis in Japan: cross-boundary dissemination and animal–human transmission of C. tropicalis infection

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

Competitiveness during Dual-Species Biofilm Formation of Fusarium oxysporum and Candida albicans and a Novel Treatment Strategy

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