A Combination Fluorescence Assay Demonstrates Increased Efflux Pump Activity as a Resistance Mechanism in Azole-Resistant Vaginal Candida albicans Isolates

Bhattacharya, Somanon; Sobel, Jack D.; White, Theodore C.

doi:10.1128/aac.01252-16

Cited by 64 publications

(48 citation statements)

References 46 publications

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“…Even though no significant correlations between efflux activity and gene expression were found in this study, Bhattacharya et al. demonstrated a good correlation between rhodamine 6G efflux assay and gene expression, by RT‐qPCR, among C . albicans from vaginal candidiasis.…”

Section: Discussioncontrasting

confidence: 78%

Azole resistance in Candida albicans from animals: Highlights on efflux pump activity and gene overexpression

Rocha

Bandeira

Alencar

et al. 2017

Mycoses

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This study investigated potential mechanisms of azole resistance among Candida albicans from animals, including efflux pump activity, ergosterol content and gene expression. For this purpose, 30 azole-resistant C. albicans strains from animals were tested for their antifungal susceptibility, according to document M27-A3, efflux pump activity by rhodamine 6G test, ergosterol content and expression of the genes CDR1, CDR2, MDR1, ERG11 by RT-qPCR. These strains were resistant to at least one azole derivative. Resistance to fluconazole and itraconazole was detected in 23 and 26 strains respectively. Rhodamine 6G tests showed increased activity of efflux pumps in the resistant strains, showing a possible resistance mechanism. There was no difference in ergosterol content between resistant and susceptible strains, even after fluconazole exposure. From 30 strains, 22 (73.3%) resistant animal strains overexpressed one or more genes. From this group, 40.9% (9/22) overexpressed CDR1, 18.2% (4/22) overexpressed CDR2, 59.1% (13/22) overexpressed MDR1 and 54.5% (12/22) overexpressed ERG11. Concerning gene expression, a positive correlation was observed only between CDR1 and CDR2. Thus, azole resistance in C. albicans strains from animals is a multifactorial process that involves increased efflux pump activity and the overexpression of different genes.

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Section: Discussioncontrasting

confidence: 78%

Azole resistance in Candida albicans from animals: Highlights on efflux pump activity and gene overexpression

Rocha

Bandeira

Alencar

et al. 2017

Mycoses

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“…Resistance by drug efflux is one of the four major mechanisms of resistance in candida. C. albicans show an overexpression of three efflux pumps: CDR1 (Cacdr1p) and CDR2 (Cacdr2p), both are ABC transporters in addition to CaMdr1p (MFS transporter) resulting in Azole resistance (Cannon et al, 2009; Bhattacharya et al, 2016; Tsao et al, 2016). …”

Section: The Atp-binding Cassette (Abc)mentioning

confidence: 99%

The Role of Eukaryotic and Prokaryotic ABC Transporter Family in Failure of Chemotherapy

Saleh²,

et al. 2017

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Over the years chemotherapy failure has been a vital research topic as researchers have been striving to discover reasons behind it. The extensive studies carried out on chemotherapeutic agents confirm that resistance to chemotherapy is a major reason for treatment failure. “Resistance to chemotherapy,” however, is a comprehensive phrase that refers to a variety of different mechanisms in which ATP-binding cassette (ABC) mediated efflux dominates. The ABC is one of the largest gene superfamily of transporters among both eukaryotes and prokaryotes; it represents a variety of genes that code for proteins, which perform countless functions, including drug efflux – a natural process that protects cells from foreign chemicals. Up to date, chemotherapy failure due to ABC drug efflux is an active research topic that continuously provides further evidence on multiple drug resistance (MDR), aiding scientists in tackling and overcoming this issue. This review focuses on drug resistance by ABC efflux transporters in human, viral, parasitic, fungal and bacterial cells and highlights the importance of the MDR permeability glycoprotein being the mutual ABC transporter among all studied organisms. Current developments and future directions to overcome this problem are also discussed.

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“…lem, particularly given the relatively limited armamentarium against fungal infections (7)(8)(9)(10)(11). In particular, azole antifungal resistance in Candida spp.…”

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confidence: 99%

In Vitro Activities of the Novel Investigational Tetrazoles VT-1161 and VT-1598 Compared to the Triazole Antifungals against Azole-Resistant Strains and Clinical Isolates of Candida albicans

Nishimoto

Wiederhold

Flowers

et al. 2019

Antimicrob Agents Chemother

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The fungal Cyp51-specific inhibitors VT-1161 and VT-1598 have emerged as promising new therapies to combat fungal infections, including Candida spp. To evaluate their in vitro activities compared to other azoles, MICs were determined by Clinical and Laboratory Standards Institute (CLSI) method for VT-1161, VT-1598, fluconazole, voriconazole, itraconazole, and posaconazole against 68 C. albicans clinical isolates well characterized for azole resistance mechanisms and mutant strains representing individual azole resistance mechanisms. VT-1161 and VT-1598 demonstrated potent activity (geometric mean MICs Յ0.15 g/ml) against predominantly fluconazole-resistant (Ն8 g/ml) isolates. However, five of 68 isolates exhibited MICs greater than six dilutions (Ͼ2 g/ml) to both tetrazoles compared to fluconazolesusceptible isolates. Four of these isolates likewise exhibited high MICs beyond the upper limit of the assay for all triazoles tested. A premature stop codon in ERG3 likely explained the high-level resistance in one isolate. VT-1598 was effective against strains with hyperactive Tac1, Mrr1, and Upc2 transcription factors and against most ERG11 mutant strains. VT-1161 MICs were elevated compared to the control strain SC5314 for hyperactive Tac1 strains and two strains with Erg11 substitutions (Y132F and Y132F&K143R) but showed activity against hyperactive Mrr1 and Upc2 strains. While mutations affecting Erg3 activity appear to greatly reduce susceptibility to VT-1161 and VT-1598, the elevated MICs of both tetrazoles for four isolates could not be explained by known azole resistance mechanisms, suggesting the presence of undescribed resistance mechanisms to triazole-and tetrazole-based sterol demethylase inhibitors.

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A Combination Fluorescence Assay Demonstrates Increased Efflux Pump Activity as a Resistance Mechanism in Azole-Resistant Vaginal Candida albicans Isolates

Cited by 64 publications

References 46 publications

Azole resistance in Candida albicans from animals: Highlights on efflux pump activity and gene overexpression

Azole resistance in Candida albicans from animals: Highlights on efflux pump activity and gene overexpression

The Role of Eukaryotic and Prokaryotic ABC Transporter Family in Failure of Chemotherapy

In Vitro Activities of the Novel Investigational Tetrazoles VT-1161 and VT-1598 Compared to the Triazole Antifungals against Azole-Resistant Strains and Clinical Isolates of Candida albicans

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