Emerging Mechanisms of Drug Resistance in Candida albicans

Prasad, Rajendra; Nair, Remya; Banerjee, Atanu

doi:10.1007/978-3-030-13035-0_6

Cited by 32 publications

(22 citation statements)

References 78 publications

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“…Aurone SH1009 exhibited considerably low IC 50 values in the inhibition of these fluconazole-resistant isolates, indicating that the highly expressed efflux pumps could be modulated by aurone SH1009. The efflux pumps CDR1 / 2 are mainly ATP-binding cassette (ABC) transporter proteins that harness the energy from ATP hydrolysis in order to extrude drug out of the yeast cell [7]. In fact, as consistent with previous studies on cancer cells, aurones selectively inhibited the pumping action of these transporters by binding with the C-terminal nucleotide-binding domain of P-glycoprotein which belongs to the ATP-binding cassette (ABC) superfamily [70, 71].…”

Section: Discussionmentioning

confidence: 99%

“…Then, amphotericin B treatment causes a loss of function mutation in ERG2 . Consequently, the final strain was a multidrug resistant strain that acquired all the three mutations and exhibited resistance to three classes of the standard antifungal drugs [7].…”

Section: Discussionmentioning

confidence: 99%

“…Resistance mechanisms have been described to these antifungals as cellular determinants that lead to drug extrusion by active efflux, altered drug targets, or drug target overexpression. However, novel drug resistance mechanisms have been recently reported as robust responses that enhance antifungal tolerance by pathways such as regulation of the oxidative or thermal stress responses [7].…”

Section: Introductionmentioning

confidence: 99%

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Chemogenomic profiling to understand the antifungal action of a bioactive aurone compound

et al. 2019

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Every year, more than 250,000 invasive candidiasis infections are reported with 50,000 deaths worldwide. The limited number of antifungal agents necessitates the need for alternative antifungals with potential novel targets. The 2-benzylidenebenzofuran-3-(2H)-ones have become an attractive scaffold for antifungal drug design. This study aimed to determine the antifungal activity of a synthetic aurone compound and characterize its mode of action. Using the broth microdilution method, aurone SH1009 exhibited inhibition against C. albicans, including resistant isolates, as well as C. glabrata, and C. tropicalis with IC50 values of 4–29 μM. Cytotoxicity assays using human THP-1, HepG2, and A549 human cell lines showed selective toxicity toward fungal cells. The mode of action for SH1009 was characterized using chemical-genetic interaction via haploinsufficiency (HIP) and homozygous (HOP) profiling of a uniquely barcoded Saccharomyces cerevisiae mutant collection. Approximately 5300 mutants were competitively treated with SH1009 followed by DNA extraction, amplification of unique barcodes, and quantification of each mutant using multiplexed next-generation sequencing. Barcode post-sequencing analysis revealed 238 sensitive and resistant mutants that significantly (FDR P values ≤ 0.05) responded to aurone SH1009. The enrichment analysis of KEGG pathways and gene ontology demonstrated the cell cycle pathway as the most significantly enriched pathway along with DNA replication, cell division, actin cytoskeleton organization, and endocytosis. Phenotypic studies of these significantly enriched responses were validated in C. albicans. Flow cytometric analysis of SH1009-treated C. albicans revealed a significant accumulation of cells in G1 phase, indicating cell cycle arrest. Fluorescence microscopy detected abnormally interrupted actin dynamics, resulting in enlarged, unbudded cells. RT-qPCR confirmed the effects of SH1009 in differentially expressed cell cycle, actin polymerization, and signal transduction genes. These findings indicate the target of SH1009 as a cell cycle-dependent organization of the actin cytoskeleton, suggesting a novel mode of action of the aurone compound as an antifungal inhibitor.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Chemogenomic profiling to understand the antifungal action of a bioactive aurone compound

et al. 2019

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“…The mechanisms of drug resistance of C. albicans include overexpression of efflux pump gene, mutation and overexpression of target protein and biofilm formation. 5) Biofilm is a complex structure composed of associated microbial cells, attached to the surface of body's tissues or biological material and restricted in the extracellular polymeric substances which are mainly composed of polysaccharides. Meanwhile, it provides many benefits for microorganism, such as controlling the flow of nutrients, protecting self from host immune system and antimicrobial agents.…”

Section: Introductionmentioning

confidence: 99%

Study on the Inhibitory Activity and Possible Mechanism of Myriocin on Clinically Relevant Drug-Resistant <i>Candida albicans</i> and Its Biofilms

Yang

Pei

et al. 2021

Biological & Pharmaceutical Bulletin

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Objective: In order to prevent and control the infection of Candida albicans, the antifungal activity, possible mechanism of myriocin against C. albicans and its biofilm were studied. Methods: The antifungal activity of myriocin was investigated by microdilution method. The effect of myriocin on fungal cell wall or membrane was evaluated by adding sorbitol, ergosterol or phytosphingosine (PHS). The damage to the cell membrane was investigated with propidium iodide (PI) staining and visualized by Scanning electron microscope (SEM). The effects on biofilms and extracellular polysaccharides (EPS) were observed by crystal violet staining method and phenol-sulfuric acid method respectively. The adhesion of C. albicans cells to hydrocarbons was tested to evaluate cell surface hydrophobic (CSH). The combined effects of myriocin and antifungal drugs commonly used in clinical practice were investigated by using the checkerboard microdilution method. Results: MICs were found to be 0.125~4 µg/ml. Myriocin was found to affect both cell wall and cell membrane. After exposure to myriocin, biofilm and EPS were found to be inhibited and removed, and the CSH was decreased. The combined fungistasis of myriocin and voriconazole (VCZ) or amphotericin B (AMB) were additive. Conclusion: Myriocin had significant antifungal activity against C. albicans, and the antifungal mechanisms might be cell wall and membrane damage. Myriocin effectively inhibited and eliminated biofilms, and its mechanism may be related to the inhibition of EPS and CSH.

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“…Current treatment for C. albicans infections mainly rely on azoles and echinocandins (Pristov and Ghannoum, 2019). The limited therapeutic option as well as the emergence of drug resistance is a matter of concern owing to the growing number of patients suffering from fungal infections (Hendrickson et al, 2019;Prasad et al, 2019). Hence, new therapeutic strategies are urgently needed.…”

Section: Discussionmentioning

confidence: 99%

Antifungal Activity and Potential Mechanism of Panobinostat in Combination With Fluconazole Against Candida albicans

Shi

Xu³

et al. 2020

Front. Microbiol.

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Su et al. Synergistic Antifungal Effect of Panobinostat in drug resistance, was found to be inhibited, and metacaspase which is related to cell apoptosis was activated (p < 0.01), whereas the synergistic effects were proven not to be related to the efflux pumps (p > 0.05). These findings might provide novel insights into the antifungal drug discovery and the treatment of candidiasis caused by C. albicans.

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Emerging Mechanisms of Drug Resistance in Candida albicans

Cited by 32 publications

References 78 publications

Chemogenomic profiling to understand the antifungal action of a bioactive aurone compound

Chemogenomic profiling to understand the antifungal action of a bioactive aurone compound

Study on the Inhibitory Activity and Possible Mechanism of Myriocin on Clinically Relevant Drug-Resistant <i>Candida albicans</i> and Its Biofilms

Antifungal Activity and Potential Mechanism of Panobinostat in Combination With Fluconazole Against Candida albicans

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