Mechanisms of Azole Potentiation: Insights from Drug Repurposing Approaches

ACS Infectious Diseases, Год журнала: 2025, Номер unknown

Опубликована: Янв. 3, 2025

The emergence of azole resistance and tolerance in pathogenic fungi has emerged as a significant public health concern, emphasizing the urgency for innovative strategies to bolster efficacy azole-based treatments. Drug repurposing stands promising practical avenue advancing antifungal therapy, with potential swift clinical translation. This review offers comprehensive overview synergistic agents uncovered through drug strategies, alongside an in-depth exploration mechanisms by which these augment potency. Drawing from mechanisms, we delineate aimed at enhancing effectiveness, such inhibiting efflux pumps elevate concentrations within fungal cells, intensifying ergosterol synthesis inhibition, mitigating cell azoles, disrupting biological processes extending beyond synthesis. is beneficial development potentiators, it meticulously examines instances provides nuanced discussions on underlying progression potentiators strategies.

Язык: Английский

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Pitavastatin Calcium Confers Fungicidal Properties to Fluconazole by Inhibiting Ubiquinone Biosynthesis and Generating Reactive Oxygen Species

Antioxidants, Год журнала: 2024, Номер 13(6), С. 667 - 667

Опубликована: Май 29, 2024

Fluconazole (FLC) is extensively employed for the prophylaxis and treatment of invasive fungal infections (IFIs). However, fungistatic nature FLC renders pathogenic fungi capable developing tolerance towards it. Consequently, converting into a fungicidal agent using adjuvants assumes significance to circumvent resistance perpetuation infections. This drug repurposing study has successfully identified pitavastatin calcium (PIT) as promising adjuvant enhancing activity from comprehensive library 2372 FDA-approved drugs. PIT could render even at concentrations low 1 μM. The median lethal dose (LD50) was determined be 103.6 mg/kg. We have discovered that achieves its synergistic effect by inhibiting 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, thereby impeding ubiquinone biosynthesis, inducing reactive oxygen species (ROS) generation, triggering apoptosis, disrupting Golgi function. Candida albicans strain demonstrated notable infect mice found effectively augmented antifungal efficacy against IFIs. an illustrative example how drugs can eliminate FLC.

Язык: Английский

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Isobavachalcone Exhibits Potent Antifungal Efficacy by Inhibiting Enolase Activity and Glycolysis in Candida albicans

ACS Infectious Diseases, Год журнала: 2024, Номер 10(8), С. 3059 - 3070

Опубликована: Июль 12, 2024

Invasive fungal diseases (IFDs) are becoming increasingly acknowledged as a significant concern linked to heightened rates of morbidity and mortality. Regrettably, the available antifungal therapies for managing IFDs constrained. Emerging evidence indicates that enolase holds promise potential target protein combating IFDs; however, there is currently deficiency in medications specifically targeting enolase. This study establishes isobavachalcone (IBC) exhibits noteworthy efficacy both vitro vivo. Moreover, our has demonstrated IBC effectively targets Eno1

Язык: Английский

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Extracellular fungal Hsp90 represents a promising therapeutic target for combating fungal infections

European Journal of Pharmaceutical Sciences, Год журнала: 2025, Номер 207, С. 107041 - 107041

Опубликована: Фев. 12, 2025

Heat shock protein 90 (Hsp90) is a pivotal virulence factor in pathogenic fungi, playing significant role conferring drug resistance. However, due to the high amino acid sequence similarity between fungal and mammalian Hsp90, targeting intracellular Hsp90 therapeutically associated with marked toxic side effects, thereby limiting clinical application. Studies have demonstrated that can be secreted as extracellular (eHsp90), which plays crucial infections. Strategies eHsp90 exhibited promising therapeutic outcomes. Unlike targeting, such antifungal approaches operate without cell penetration, circumventing effects Hsp90's conservation. This review summarizes potential secretion pathways of eHsp90, its roles pathogenesis, well development vaccines antibodies eHsp90. The underlines significance infections suggests represents target for infection treatment.

Язык: Английский

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Extracellular Hsp90 of Candida albicans contributes to the virulence of the pathogen by activating the NF-κB signaling pathway and inducing macrophage pyroptosis

Microbiological Research, Год журнала: 2024, Номер 290, С. 127964 - 127964

Опубликована: Ноя. 5, 2024

Язык: Английский

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A Causal Relationship between Type 2 Diabetes and Candidiasis through Two-Sample Mendelian Randomization Analysis

Microorganisms, Год журнала: 2024, Номер 12(10), С. 1984 - 1984

Опубликована: Сен. 30, 2024

The potential relationship between type 2 diabetes (T2D) and candidiasis is of concern due to the respective characteristics these conditions, yet exact causal link two remains uncertain requires further investigation. In this study, inverse-variance-weighted (IVW) analysis indicated a significant genetic T2D (

Язык: Английский

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