Mechanisms of Azole Potentiation: Insights from Drug Repurposing Approaches.

IF 4 2区医学 Q2 CHEMISTRY, MEDICINAL

ACS Infectious Diseases Pub Date : 2025-01-03 DOI:10.1021/acsinfecdis.4c00657

Juan Xiong, Hui Lu, Yuanying Jiang

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引用次数: 0

Abstract

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

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病原真菌对唑类耐药性和耐受性的出现已成为一个重大的公共卫生问题，这凸显了采取创新策略提高唑类治疗效果的紧迫性。药物再利用是推进抗真菌治疗的一条前景广阔的实用途径，具有迅速转化为临床治疗的潜力。本综述全面概述了通过药物再利用战略发现的唑类增效剂，并深入探讨了这些药物增强唑类药效的机制。根据这些机制，我们阐述了旨在增强唑类药效的策略，如抑制外排泵以提高真菌细胞内的唑类浓度、加强麦角甾醇合成抑制、减轻真菌细胞对唑类的抗性以及破坏麦角甾醇合成以外的生物过程。这篇综述对这些增效剂的开发大有裨益，因为它细致地研究了唑类增效剂通过药物再利用战略取得进展的实例，并对其背后的机制进行了细致入微的讨论。

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来源期刊

ACS Infectious Diseases CHEMISTRY, MEDICINALINFECTIOUS DISEASES&nb-INFECTIOUS DISEASES

CiteScore

9.70

自引率

3.80%

发文量

213

期刊介绍： ACS Infectious Diseases will be the first journal to highlight chemistry and its role in this multidisciplinary and collaborative research area. The journal will cover a diverse array of topics including, but not limited to: * Discovery and development of new antimicrobial agents — identified through target- or phenotypic-based approaches as well as compounds that induce synergy with antimicrobials. * Characterization and validation of drug target or pathways — use of single target and genome-wide knockdown and knockouts, biochemical studies, structural biology, new technologies to facilitate characterization and prioritization of potential drug targets. * Mechanism of drug resistance — fundamental research that advances our understanding of resistance; strategies to prevent resistance. * Mechanisms of action — use of genetic, metabolomic, and activity- and affinity-based protein profiling to elucidate the mechanism of action of clinical and experimental antimicrobial agents. * Host-pathogen interactions — tools for studying host-pathogen interactions, cellular biochemistry of hosts and pathogens, and molecular interactions of pathogens with host microbiota. * Small molecule vaccine adjuvants for infectious disease. * Viral and bacterial biochemistry and molecular biology.