Faculty Opinions recommendation of Structure-guided development of efficacious antifungal agents targeting Candida glabrata dihydrofolate reductase.

ABSTRACT Candida glabrata has recently emerged as a significant pathogen involved in both superficial and deep-seated infections. In the present study, a checkerboard broth microdilution method was performed to investigate the in vitro activities of voriconazole (VOR) in combination with terbinafine (TRB), amphotericin B (AMB), and flucytosine (5FC) against 20 clinical isolates of C. glabrata. Synergy, defined as a fractional inhibitory concentration (FIC) index of ≤0.50, was observed in 75% of VOR-TRB, 10% of VOR-AMB, and 5% of VOR-5FC interactions. None of these combinations yielded antagonistic interactions (FIC index > 4). When synergy was not achieved, there was still a decrease in the MIC of one or both drugs used in the combination. In particular, the MICs were reduced to ≤1.0 μg/ml as a result of the combination for all isolates for which the AMB MIC at the baseline was ≥2.0 μg/ml. By a disk diffusion assay, the halo diameters produced by antifungal agents in combination were greater that those produced by each drug alone. Finally, killing curves showed that VOR-AMB exhibited synergistic interactions, while VOR-5FC sustained fungicidal activities against C. glabrata. These studies demonstrate that the in vitro activity of VOR against this important yeast pathogen can be enhanced upon combination with other drugs that have different modes of action or that target a different step in the ergosterol pathway. Further studies are warranted to elucidate the potential beneficial effects of such combination regimens in vivo.

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Antifungal Activity of SCY-078 and Standard Antifungal Agents against 178 Clinical Isolates of Resistant and Susceptible Candida Species

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01102-17 ◽

2017 ◽

Vol 61 (11) ◽

Cited By ~ 20

Author(s):

Wiley A. Schell ◽

A. M. Jones ◽

Katyna Borroto-Esoda ◽

Barbara D. Alexander

Keyword(s):

Candida Glabrata ◽

Antifungal Agents ◽

Candida Parapsilosis ◽

Candida Krusei ◽

Wild Type ◽

Content Type ◽

Clinical Resistance ◽

Excellent Activity ◽

Candida Lusitaniae

ABSTRACT SCY-078 in vitro activity was determined for 178 isolates of resistant or susceptible Candida albicans, Candida dubliniensis, Candida glabrata, Candida krusei, Candida lusitaniae, and Candida parapsilosis, including 44 Candida isolates with known genotypic (FKS1 or FKS2 mutations), phenotypic, or clinical resistance to echinocandins. Results were compared to those for anidulafungin, caspofungin, micafungin, fluconazole, and voriconazole. SCY-078 was shown to have excellent activity against both wild-type isolates and echinocandin- and azole-resistant isolates of Candida species.

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Effects of Antifungal Agents Alone and in Combination Against Candida glabrata Strains Susceptible or Resistant to Fluconazole

Mycopathologia ◽

10.1007/s11046-012-9538-7 ◽

2012 ◽

Vol 174 (3) ◽

pp. 215-221 ◽

Cited By ~ 10

Author(s):

Izabel Almeida Alves ◽

Laíssa Arévalo Bandeira ◽

Débora Alves Nunes Mario ◽

Laura Bedin Denardi ◽

Louise Vignoles Neves ◽

...

Keyword(s):

Candida Glabrata ◽

Antifungal Agents

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Jjj1 Is a Negative Regulator of Pdr1-Mediated Fluconazole Resistance in Candida glabrata

mSphere ◽

10.1128/msphere.00466-17 ◽

2018 ◽

Vol 3 (1) ◽

Cited By ~ 6

Author(s):

Sarah G. Whaley ◽

Kelly E. Caudle ◽

Lucia Simonicova ◽

Qing Zhang ◽

W. Scott Moye-Rowley ◽

...

Keyword(s):

Fungal Pathogen ◽

Candida Glabrata ◽

Antifungal Agents ◽

Common Species ◽

Negative Regulator ◽

Gene Encoding ◽

Fluconazole Resistance ◽

Mechanism Of Resistance ◽

Primary Mechanism ◽

Activating Mutation

Candida glabrata is the second most common species of Candida recovered from patients with invasive candidiasis. The increasing number of infections due to C. glabrata, combined with its high rates of resistance to the commonly used, well-tolerated azole class of antifungal agents, has limited the use of this antifungal class. This has led to the preferential use of echinocandins as empirical treatment for serious Candida infections. The primary mechanism of resistance found in clinical isolates is the presence of an activating mutation in the gene encoding the transcription factor Pdr1 that results in upregulation of one or more of the efflux pumps Cdr1, Pdh1, and Snq2. By developing a better understanding of this mechanism of resistance to the azoles, it will be possible to develop strategies for reclaiming the utility of the azole antifungals against this important fungal pathogen.

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Resistance to echinocandin antifungal agents in the United Kingdom in clinical isolates of Candida glabrata: Fifteen years of interpretation and assessment

Medical Mycology ◽

10.1093/mmy/myz053 ◽

2019 ◽

Cited By ~ 4

Author(s):

Mark Fraser ◽

Andrew M Borman ◽

Robin Thorn ◽

Lynne M Lawrance

Keyword(s):

United Kingdom ◽

Candida Glabrata ◽

Antifungal Agents ◽

Clinical Isolates ◽

The United Kingdom

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Role of ATP-Binding-Cassette Transporter Genes in High-Frequency Acquisition of Resistance to Azole Antifungals in Candida glabrata

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.45.4.1174-1183.2001 ◽

2001 ◽

Vol 45 (4) ◽

pp. 1174-1183 ◽

Cited By ~ 169

Author(s):

Dominique Sanglard ◽

Francoise Ischer ◽

Jacques Bille

Keyword(s):

Abc Transporter ◽

High Frequency ◽

Candida Glabrata ◽

Antifungal Agents ◽

Clinical Isolates ◽

Azole Resistance ◽

Atp Binding ◽

Transporter Gene ◽

Atp Binding Cassette

ABSTRACT Candida glabrata has been often isolated from AIDS patients with oropharyngeal candidiasis treated with azole antifungal agents, especially fluconazole. We recently showed that the ATP-binding-cassette (ABC) transporter gene CgCDR1 was upregulated in C. glabrata clinical isolates resistant to azole antifungal agents (D. Sanglard, F. Ischer, D. Calabrese, P. A. Majcherczyk, and J. Bille, Antimicrob. Agents Chemother. 43:2753–2765, 1999). Deletion of CgCDR1 in C. glabrata rendered the null mutant hypersusceptible to azole derivatives and showed the importance of this gene in mediating azole resistance. We observed that wild-type C. glabrata exposed to fluconazole in a medium containing the drug at 50 μg/ml developed resistance to this agent and other azoles at a surprisingly high frequency (2 × 10−4 to 4 × 10−4). We show here that this high-frequency azole resistance (HFAR) acquired in vitro was due, at least in part, to the upregulation ofCgCDR1. The CgCDR1 deletion mutant DSY1041 could still develop HFAR but in a medium containing fluconazole at 5 μg/ml. In the HFAR strain derived from DSY1041, a distinct ABC transporter gene similar to CgCDR1, calledCgCDR2, was upregulated. This gene was slightly expressed in clinical isolates but was upregulated in strains with the HFAR phenotype. Deletion of both CgCDR1 and CgCDR2suppressed the development of HFAR in a medium containing fluconazole at 5 μg/ml, showing that both genes are important mediators of resistance to azole derivatives in C. glabrata. We also show here that the HFAR phenomenon was linked to the loss of mitochondria in C. glabrata. Mitochondrial loss could be obtained by treatment with ethidium bromide and resulted in acquisition of resistance to azole derivatives without previous exposure to these agents. Azole resistance obtained in vitro by HFAR or by agents stimulating mitochondrial loss was at least linked to the upregulation of both CgCDR1 and CgCDR2.

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Effect of antifungals on itraconazole resistant Candida glabrata

Open Life Sciences ◽

10.2478/s11535-010-0021-5 ◽

2010 ◽

Vol 5 (3) ◽

pp. 318-323 ◽

Cited By ~ 1

Author(s):

Soňa Kucharíková ◽

Patrick Dijck ◽

Magdaléna Lisalová ◽

Helena Bujdáková

Keyword(s):

Amphotericin B ◽

Biofilm Formation ◽

Candida Glabrata ◽

Antifungal Agents ◽

Inhibitory Concentration ◽

Clinical Isolates ◽

Azole Resistance ◽

Low Concentrations ◽

Reduction Assay ◽

Very High

AbstractIn the last decade, infections caused by Candida glabrata have become more serious, particularly due to its decreased susceptibility to azole derivatives and its ability to form biofilm. Here we studied the resistance profile of 42 C. glabrata clinical isolates to different azoles, amphotericin B and echinocandins. This work was also focused on the ability to form biofilm which plays a role in the development of antifungal resistance. The minimal inhibitory concentration testing to antifungal agents was performed according to the CLSI (Clinical and Laboratory Standards Institute) M27-A3 protocol. Quantification of biofilm was done by XTT reduction assay. All C. glabrata clinical isolates were resistant to itraconazole and sixteen also showed resistance to fluconazole. All isolates remained susceptible to voriconazole. Amphotericin B was efficient in a concentration range of 0.125–1 mg/L. The most effective antifungal agents were micafungin and caspofungin with the MIC100 values of ≤0.0313–0.125 mg/L. Low concentrations of these agents reduced biofilm formation as well. Our results show that resistance of different C. glabrata strains is azole specific and therefore a single azole resistance cannot be assumed to indicate general azole resistance. Echinocandins proved to have very high efficacy against clinical C. glabrata strains including those with ability to form biofilm.

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Inhibition of recombinant enzyme 3-hydroxy-3-methylglutaryl-CoA reductase from Candida glabrata by α-asarone-based synthetic compounds as antifungal agents

Journal of Biotechnology ◽

10.1016/j.jbiotec.2019.01.008 ◽

2019 ◽

Vol 292 ◽

pp. 64-67 ◽

Cited By ~ 2

Author(s):

Dulce Andrade-Pavón ◽

Jossue Ortiz-Álvarez ◽

Eugenia Sánchez-Sandoval ◽

Joaquín Tamariz ◽

César Hernández-Rodríguez ◽

...

Keyword(s):

Candida Glabrata ◽

Antifungal Agents ◽

Recombinant Enzyme ◽

Synthetic Compounds ◽

Coa Reductase

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Effect of pH onIn VitroSusceptibility of Candida glabrata and Candida albicans to 11 Antifungal Agents and Implications for Clinical Use

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.05025-11 ◽

2012 ◽

Vol 56 (3) ◽

pp. 1403-1406 ◽

Cited By ~ 49

Author(s):

Claire S. Danby ◽

Dina Boikov ◽

Rina Rautemaa-Richardson ◽

Jack D. Sobel

Keyword(s):

Amphotericin B ◽

Candida Glabrata ◽

Antifungal Agents ◽

Susceptibility Testing ◽

Low Ph ◽

Clinical Use ◽

Effect Of Ph ◽

Content Type ◽

Clinical Observations

ABSTRACTThe treatment of vulvovaginal candidiasis (VVC) due toCandida glabratais challenging, with limited therapeutic options. Unexplained disappointing clinical efficacy has been reported with systemic and topical azole antifungal agents in spite ofin vitrosusceptibility. Given that the vaginal pH of patients with VVC is unchanged at 4 to 4.5, we studied the effect of pH on thein vitroactivity of 11 antifungal agents against 40C. glabrataisolates and compared activity against 15 fluconazole-sensitive and 10 reduced-fluconazole-susceptibilityC. albicansstrains.In vitrosusceptibility to flucytosine, fluconazole, voriconazole, posaconazole, itraconazole, ketoconazole, clotrimazole, miconazole, ciclopirox olamine, amphotericin B, and caspofungin was determined using the CLSI method for yeast susceptibility testing. Test media were buffered to pHs of 7, 6, 5, and 4. Under conditions of reduced pH,C. glabrataisolates remained susceptible to caspofungin and flucytosine; however, there was a dramatic increase in the MIC90for amphotericin B and every azole drug tested. Although susceptible to other azole drugs tested at pH 7,C. albicansstrains with reduced fluconazole susceptibility also demonstrated reduced susceptibility to amphotericin B and all azoles at pH 4. In contrast, fluconazole-sensitiveC. albicansisolates remained susceptible at low pH to azoles, in keeping with clinical observations. In selecting agents for treatment of recurrentC. glabratavaginitis, clinicians should recognize the limitations ofin vitrosusceptibility testing utilizing pH 7.0.

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