scholarly journals Pyrogallol and Fluconazole Interact Synergistically In Vitro Against Candida glabrata Through an Efflux-Associated Mechanism

2021 ◽  
Author(s):  
Dongting Yao ◽  
Guanyi Zhang ◽  
Weiqin Chen ◽  
Jia Chen ◽  
Zhen Li ◽  
...  
Keyword(s):  
Candida Glabrata ◽  
Antifungal Agents ◽  
Inhibitory Concentration ◽  
Rhodamine 6G ◽  
Pcr Analysis ◽  
Potential Mechanism ◽  
Combination Therapies ◽  
Qrt Pcr ◽  
Susceptibility Tests

Candida glabrata is currently the first or second most commonly encountered non-albicans Candida species worldwide. The potential severity of Candida resistance mandates the discovery of novel antifungal agents, including those that can be used in combination therapies. In this study, we evaluated the in vitro interactions of pyrogallol (PG) and azole drugs against 22 clinical C. glabrata isolates. The potential mechanism underlying the synergism between PG and fluconazole (FLC) was investigated by the rhodamine 6G efflux method and quantitative reverse transcription (qRT)-PCR analysis. In susceptibility tests, PG showed strong synergism with FLC, itraconazole (ITC), and voriconazole (VRC), with fractional inhibitory concentration index values of 0.188–0.375 for PG+FLC, 0.250–0.750 for PG+ITC, and 0.141–0.750 for PG+VRC. Cells grown in the presence of PG+FLC exhibited reduced rhodamine 6G extrusion and significantly downregulated expression of the efflux-related genes CgCDR1, CgCDR2, and CgPDR1 when compared with cells grown in the presence of PG or FLC alone. PG did not potentiate FLC when tested against a ΔCgpdr1 strain. Restoration of a functional CgPDR1 allele also restored the synergism. These results indicate that PG is an antifungal agent that synergistically potentiates the activity of azoles. Further, PG appears to exert its effects by inhibiting efflux pumps and by downregulating CgCDR1, CgCDR2, and CgPDR1, with CgPDR1 probably playing a crucial role in this process.

scholarly journals In Vitro Activities of Voriconazole in Combination with Three Other Antifungal Agents against Candida glabrata

2004 ◽  
Vol 48 (9) ◽  
pp. 3317-3322 ◽  
Author(s):  
Francesco Barchiesi ◽  
Elisabetta Spreghini ◽  
Monia Maracci ◽  
Annette W. Fothergill ◽  
Isabella Baldassarri ◽  
...  
Keyword(s):  
Candida Glabrata ◽  
Antifungal Agents ◽  
Beneficial Effects ◽  
Synergistic Interactions ◽  
Microdilution Method ◽  
Broth Microdilution Method ◽  
Disk Diffusion Assay ◽  
Combination Regimens

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.

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

2017 ◽  
Vol 61 (11) ◽  
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.

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

2001 ◽  
Vol 45 (4) ◽  
pp. 1174-1183 ◽  
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.

scholarly journals In Vitro Interaction of Posaconazole and Caspofungin against Clinical Isolates of Candida glabrata

2005 ◽  
Vol 49 (8) ◽  
pp. 3544-3545 ◽  
Author(s):  
E. R. Oliveira ◽  
A. W. Fothergill ◽  
W. R. Kirkpatrick ◽  
B. J. Coco ◽  
T. F. Patterson ◽  
...  
Keyword(s):  
Candida Glabrata ◽  
Concentration Index ◽  
Inhibitory Concentration ◽  
Clinical Isolates ◽  
Fractional Inhibitory Concentration ◽  
Fractional Inhibitory Concentration Index ◽  
Fluconazole Resistant ◽  
In Vitro Interaction

ABSTRACT Combinations of caspofungin and posaconazole were evaluated by fractional inhibitory concentration index against 119 Candida glabrata isolates. Synergy was seen in 18% of all isolates and in 4% of fluconazole-resistant isolates at 48 h without evidence of antagonism. This antifungal combination may have utility against this organism.

Effect of antifungals on itraconazole resistant Candida glabrata

2010 ◽  
Vol 5 (3) ◽  
pp. 318-323 ◽  
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.

scholarly journals 7-Chloroquinolin-4-yl Arylhydrazone Derivatives: Synthesis and Antifungal Activity

2011 ◽  
Vol 11 ◽  
pp. 1489-1495 ◽  
Author(s):  
Auri R. Duval ◽  
Pedro H. Carvalho ◽  
Maieli C. Soares ◽  
Daniela P. Gouvêa ◽  
Geonir M. Siqueira ◽  
...  
Keyword(s):  
Antifungal Activity ◽  
Rational Design ◽  
Antifungal Agents ◽  
Inhibitory Concentration ◽  
First Line ◽  
Minimum Fungicidal Concentration ◽  
Starting Point ◽  
Line Drug ◽  
In Vitro Antifungal Activity

Fifteen 7-chloro-4-arylhydrazonequinolines have been evaluated for their in vitro antifungal activity against eight oral fungi:Candida albicans, C. parapsilosis, C. lipolytica, C. tropicalis, C. famata, C. glabrata, Rhodutorula mucilaginosa, andR. glutinis. Several compounds exhibited minimum inhibitory concentration (MIC) and minimum fungicidal concentration (MFC) activities comparable with the first-line drug fluconazole. These results could be considered as an important starting point for the rational design of new antifungal agents.

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

2012 ◽  
Vol 56 (3) ◽  
pp. 1403-1406 ◽  
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.

scholarly journals Antifungal agents in non-neonatologic pediatrics

2013 ◽  
Vol 4 (1S) ◽  
pp. 45-50
Author(s):  
Elio Castagnola
Keyword(s):  
Minimal Inhibitory Concentration ◽  
Amphotericin B ◽  
Antifungal Agent ◽  
Antifungal Agents ◽  
Inhibitory Concentration ◽  
Time Dependent ◽  
Combination Therapies ◽  
Agent Interactions

The spectrum of action of antifungal agents helps driving the choice of the treatment, basing on the activity against the fungus of interest. Pharmacokinetics should also be taken into account, considering the time-dependent and the concentration-dependent drugs. Triazoles belong to the first group, while amphotericin B and echinocandins belong to the second one. The effectiveness of time-dependent drugs hangs on the time spent above the Minimal Inhibitory Concentration (MIC), whereas that of concentration-dependent drugs is related to the peak of concentration achieved. Thetissue penetration is another important factor that should be taken into account while prescribing an antifungal agent. Interactions with other drugs, above all with those used to treat underlying pathologies, should also be considered. Fungicidal drugs are generally preferred to fungistatic agents, therefore echinocandins and amphotericin B are more prescribed than azoles. Combination therapies are not recommended.

scholarly journals Inhibition of MIR4435-2HG on Invasion, Migration, and EMT of Gastric Carcinoma Cells by Mediating MiR-138-5p/Sox4 Axis

2021 ◽  
Vol 11 ◽  
Author(s):  
Li-Fei Gao ◽  
Wei Li ◽  
Ya-Gang Liu ◽  
Cui Zhang ◽  
Wei-Na Gao ◽  
...  
Keyword(s):  
Gastric Carcinoma ◽  
Tumor Growth ◽  
Epithelial Mesenchymal Transition ◽  
Carcinoma Cells ◽  
The Cancer Genome Atlas ◽  
Cell Counting ◽  
Pcr Analysis ◽  
Mesenchymal Transition ◽  
Qrt Pcr

BackgroundThe previous investigations have identified that long non-coding RNA (lncRNAs) act as crucial regulators in gastric carcinoma. However, the function of lncRNA MIR4435-2HG in the modulation of gastric carcinoma remains elusive. Here, we aimed to explore the role of MIR4435-2HG in gastric carcinoma.MethodThe Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) were applied to select the differently expressed lncRNAs in gastric carcinoma. The qRT-PCR was applied to analyze MIR4435-2HG expression in carcinoma tissues and cell lines. The effect of MIR4435-2HG on proliferation, invasion, migration, and apoptosis of gastric carcinoma cells was detected by Cell Counting Kit-8 (CCK-8) assays, transwell assays, and flow cytometry in vitro. A subcutaneous tumor model was constructed to examine the tumor growth of gastric carcinoma cells after knocking out MIR4435-2HG. RNA immunoprecipitation and luciferase reporting assays were applied to evaluate the interaction of MIR4435-2HG, miR-138-5p, and Sox4.ResultsThe bioinformatics analysis based on TCGA and GEO databases indicated that MIR4435-2HG was obviously elevated in gastric carcinoma samples. The qRT-PCR analysis revealed that MIR4435-2HG was upregulated in clinical gastric carcinoma tissues and cells. The high expression of MIR4435-2HG is associated with the poor survival rate of patients. The knockout of MIR4435-2HG could repress the proliferation, invasion, migration, and epithelial–mesenchymal transition (EMT) and accelerate the apoptosis of gastric carcinoma cells. Moreover, the deletion of MIR4435-2HG was able to attenuate the tumor growth in vivo. Mechanically, we identified that MIR4435-2HG enhanced Sox4 expression by directly interacting with miR-138-5p as a competitive endogenous RNA (ceRNA) in gastric carcinoma cells, in which Sox4 was targeted by miR-138-5p.ConclusionMIR4435-2HG is elevated in gastric carcinoma cells and contributes to the growth, metastasis, and EMT of gastric carcinoma cells by targeting miR-138-5p/Sox4 axis. MIR4435-2HG may be applied as a potential therapeutic target in gastric carcinoma.

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