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Antifungal drug discovery: the process and outcomes

TLDR
The dogma on antifungal discovery is examined and it is suggested that a major thrust in technologies such as structural biology, homology modeling and virtual imaging is needed to drive discovery.
Abstract
Abstr A ct: New data suggest that the global incidence of several types of fungal diseases have traditionally been under-documented. Of these, mortality caused by invasive fungal infections remains disturbingly high, equal to or exceeding deaths caused by drug-resistant tuberculosis and malaria. It is clear that basic research on new antifungal drugs, vaccines and diagnostic tools is needed. In this review, we focus upon antifungal drug discovery including in vitro assays, compound libraries and approaches to target identification. Genome mining has made it possible to identify fungal-specific targets; however, new compounds to these targets are apparently not in the antimicrobial pipeline. We suggest that ‘repurposing’ compounds (off patent) might be a more immediate starting point. Furthermore, we examine the dogma on antifungal discovery and suggest that a major thrust in technologies such as structural biology, homology modeling and virtual imaging is needed to drive discovery.

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History of the development of antifungal azoles: A review on structures, SAR, and mechanism of action.

TL;DR: This review summarized the state-of-the-art information about azole drugs, with a specific focus on those in the pipelines of pharmaceutical companies, into four generations with regard to their structural similarity, and highlights information on the structure activity relationship (SAR), target description, hybrid antifungal agents as possible future generation.
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Combined Antifungal Resistance and Biofilm Tolerance: the Global Threat of Candida auris.

TL;DR: The clinical importance of antifungal resistance in C. auris is highlighted and the current understanding of the mechanisms associated with azole, polyene, and echinocandin resistance is explored.
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The Antifungal Activity of Naphthoquinones: An Integrative Review

TL;DR: The objective of this review is to describe the development of naphthoquinones as antifungals for the treatment of Candida species and to note the most promising compounds.
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System-level impact of mitochondria on fungal virulence: to metabolism and beyond

TL;DR: A review of likely mechanisms of mitochondrial impact on fungal virulence pathways through metabolism and stress responses, but also potentially via control over signaling pathways, and highlights fungal mitochondrial proteins that lack human homologs and which could be inhibited as a novel approach to antifungal drug strategy.
References
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Journal ArticleDOI

Hidden Killers: Human Fungal Infections

TL;DR: The importance of fungi as human pathogens is highlighted and the challenges the authors face in combating the devastating invasive infections caused by these microorganisms are discussed, in particular in immunocompromised individuals.
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The druggable genome

TL;DR: An assessment of the number of molecular targets that represent an opportunity for therapeutic intervention is crucial to the development of post-genomic research strategies within the pharmaceutical industry.
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Candida species: current epidemiology, pathogenicity, biofilm formation, natural antifungal products and new therapeutic options

TL;DR: A brief review of the literature regarding the epidemiology of Candida species, as well as their pathogenicity and ability to form biofilms, the antifungal activity of natural products and other therapeutic options is presented.
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Development of Interpretive Breakpoints for Antifungal Susceptibility Testing: Conceptual Framework and Analysis of In Vitro-In Vivo Correlation Data for Fluconazole, Itraconazole, and Candida Infections

TL;DR: The conceptual framework underlying interpretation of antimicrobial susceptibility testing results is examined and these ideas are used to drive analysis of data packages developed by the respective manufacturers that correlate fluconazole and itraconazole MICs with outcome of candidal infections.
Journal ArticleDOI

Antifungal drug resistance: mechanisms, epidemiology, and consequences for treatment.

TL;DR: Standardized methods for reliable in vitro antifungal susceptibility testing are now available from the Clinical and Laboratory Standards Institute (CLSI) in the United States and the European Committee on Antimicrobial Susceptibility Testing (EUCAST) in Europe.
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