In vitro synergy of isavuconazole in combination with colistin against Candida auris

Schwarz, Patrick; Bidaud, Anne-Laure; Dannaoui, Éric

doi:10.1038/s41598-020-78588-5

Cited by 27 publications

(25 citation statements)

References 50 publications

(61 reference statements)

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“… 24 − 26 Colsitin is generally not considered an antifungal drug, although it has weak antifungal activity in Candida tropicalis ( 27 ) and when used in combination with the azole isavuconazole in C. auris . 28 …”

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confidence: 99%

Combining Colistin and Fluconazole Synergistically Increases Fungal Membrane Permeability and Antifungal Cidality

et al. 2021

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The increasing emergence of drug-resistant fungal pathogens, together with the limited number of available antifungal drugs, presents serious clinical challenges to treating systemic, life-threatening infections. Repurposing existing drugs to augment the antifungal activity of well-tolerated antifungals is a promising antifungal strategy with the potential to be implemented rapidly. Here, we explored the mechanism by which colistin, a positively charged lipopeptide antibiotic, enhances the antifungal activity of fluconazole, the most widely used orally available antifungal. In a range of susceptible and drug-resistant isolates and species, colistin was primarily effective at reducing fluconazole tolerance, a property of subpopulations of cells that grow slowly in the presence of a drug and may promote the emergence of persistent infections and resistance. Clinically relevant concentrations of colistin synergized with fluconazole, reducing fluconazole minimum inhibitory concentration 4-fold. Combining fluconazole and colistin also increased survival in a C. albicans Galleria mellonella infection, especially for a highly fluconazole-tolerant isolate. Mechanistically, colistin increased permeability to fluorescent antifungal azole probes and to intracellular dyes, accompanied by an increase in cell death that was dependent upon pharmacological or genetic inhibition of the ergosterol biosynthesis pathway. The positive charge of colistin is critical to its antifungal, and antibacterial, activity: colistin directly binds to several eukaryotic membrane lipids ( i.e. , l -α-phosphatidylinositol, l -α-phosphatidyl- l -serine, and l -α-phosphatidylethanolamine) that are enriched in the membranes of ergosterol-depleted cells. These results support the idea that colistin binds to fungal membrane lipids and permeabilizes fungal cells in a manner that depends upon the degree of ergosterol depletion.

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confidence: 99%

Combining Colistin and Fluconazole Synergistically Increases Fungal Membrane Permeability and Antifungal Cidality

et al. 2021

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“…To date, there is no solid consensus about which endpoint should be used, particularly when one of the drugs tested is not a traditional antifungal agent, which is the case in this study. In addition, it is particularly true in the case of biofilms where metabolic activity-based susceptibility tests are generally used [ 69 ]. Based on the molecular background of the synergism, BM pre-treatment of C. albicans cells significantly influenced and enhanced the gene expression changes recorded in MSB-treated WT cells, whereas MSB alone showed moderate effects on the transcripts’ levels ( Figure 2 and Figure 3 , Table 2 ).…”

Section: Discussionmentioning

confidence: 99%

The Negative Effect of Protein Phosphatase Z1 Deletion on the Oxidative Stress Tolerance of Candida albicans Is Synergistic with Betamethasone Exposure

Jakab

Emri

Csillag

et al. 2021

JoF

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The glucocorticoid betamethasone (BM) has potent anti-inflammatory and immunosuppressive effects; however, it increases the susceptibility of patients to superficial Candida infections. Previously we found that this disadvantageous side effect can be counteracted by menadione sodium bisulfite (MSB) induced oxidative stress treatment. The fungus specific protein phosphatase Z1 (CaPpz1) has a pivotal role in oxidative stress response of Candida albicans and was proposed as a potential antifungal drug target. The aim of this study was to investigate the combined effects of CaPPZ1 gene deletion and MSB treatment in BM pre-treated C. albicans cultures. We found that the combined treatment increased redox imbalance, enhanced the specific activities of antioxidant enzymes, and reduced the growth in cappz1 mutant (KO) strain. RNASeq data demonstrated that the presence of BM markedly elevated the number of differentially expressed genes in the MSB treated KO cultures. Accumulation of reactive oxygen species, increased iron content and fatty acid oxidation, as well as the inhibiting ergosterol biosynthesis and RNA metabolic processes explain, at least in part, the fungistatic effect caused by the combined stress exposure. We suggest that the synergism between MSB treatment and CaPpz1 inhibition could be considered in developing of a novel combinatorial antifungal strategy accompanying steroid therapy.

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“…They discovered promising synergistic interactions for two couples: micafungin/voriconazole and micafungin/fluconazole. This strategy has also been demonstrated recently by the in vitro synergistic combination of isavuconazole (azole derivative) with colistin [ 62 ].…”

Section: Combination Drugsmentioning

confidence: 99%

Promising Drug Candidates and New Strategies for Fighting against the Emerging Superbug Candida auris

et al. 2021

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Invasive fungal infections represent an expanding threat to public health. During the past decade, a paradigm shift of candidiasis from Candida albicans to non-albicans Candida species has fundamentally increased with the advent of Candida auris. C. auris was identified in 2009 and is now recognized as an emerging species of concern and underscores the urgent need for novel drug development strategies. In this review, we discuss the genomic epidemiology and the main virulence factors of C. auris. We also focus on the different new strategies and results obtained during the past decade in the field of antifungal design against this emerging C. auris pathogen yeast, based on a medicinal chemist point of view. Critical analyses of chemical features and physicochemical descriptors will be carried out along with the description of reported strategies.

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In vitro synergy of isavuconazole in combination with colistin against Candida auris

Cited by 27 publications

References 50 publications

Combining Colistin and Fluconazole Synergistically Increases Fungal Membrane Permeability and Antifungal Cidality

Combining Colistin and Fluconazole Synergistically Increases Fungal Membrane Permeability and Antifungal Cidality

The Negative Effect of Protein Phosphatase Z1 Deletion on the Oxidative Stress Tolerance of Candida albicans Is Synergistic with Betamethasone Exposure

Promising Drug Candidates and New Strategies for Fighting against the Emerging Superbug Candida auris

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