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Published on: December 5, 2020
Natural Products as Antifungal Agents against Invasive Fungi
Fang-Rui Dong1,2,3, Lu Gao4,5, Liang Wang6
1Center for New Drug Research, School of Pharmacy, Naval Medical University, Shanghai, China.
Background:
Invasive fungal infections (IFIs) are primarily caused by Candida spp., Cryptococcus neoformans, Aspergillus spp., Mucor spp., Sporothrix spp., and Pneumocystis spp., which attack human organs with a strong pathogenicity and exhibit drug resistance against commonly used chemical drugs. Therefore, the search for alternative drugs with high efficacy, low resistance rates, few side effects, and synergistic antifungal effects remains a major challenge. The characteristics of natural products with structural and bioactive diversity, lower drug resistance, and rich resources make them a major focus of the development of antifungal drugs.
Objectives:
This review attempts to summarize the origin, structure, and antifungal activity of natural products and their derivatives with MIC ≤ 20 μg/mL or 100 μM, focusing on their MoA and SAR.
Methods:
All pertinent literature databases were searched. The search keywords were antifungal or antifungals, terpenoids, steroidal saponins, alkaloid, phenols, lignans, flavonoids, quinones, macrolide, peptide, tetramic acid glycoside, polyene, polyketide, bithiazole, natural product, and derivatives. All the related literature (covering the past 20 years, 2001-2022) was evaluated.
Results:
In total, 340 natural products and 34 synthesized derivatives with antifungal activity from 301 studies were included in this review. These compounds were derived from terrestrial plants, ocean life, and microorganisms and exhibited in vitro and in vivo potent antifungal activity alone or in combination. The MoA and SARs of reported compounds were summarized whenever applicable.
Conclusion:
In this review, we attempted to review the available literature on natural antifungal products and their derivatives. Most of the studied compounds showed potent activity against Candida species, Aspergillus species, or Cryptococcus species. Some of the studied compounds also demonstrated the ability to impair the cell membrane and cell wall, inhibit hypha and biofilms, and cause mitochondrial dysfunction. Although the MoAs of these compounds are not well understood yet, they can be used as lead components for the development of new, effective, and safe antifungal agents through their novel mechanisms.
Insights
Natural products offer promising alternatives to combat drug-resistant invasive fungal infections (IFIs). This review highlights their diverse antifungal activities and potential as novel therapeutic agents.
Area of Science:
- Medicinal Chemistry
- Pharmacology
- Natural Products Chemistry
Background:
- Invasive fungal infections (IFIs) pose a significant threat due to pathogenic fungi like *Candida*, *Cryptococcus*, and *Aspergillus* species exhibiting resistance to conventional antifungal drugs.
- The urgent need for novel antifungal agents with high efficacy, low resistance, and minimal side effects drives research into alternative sources.
- Natural products, with their diverse structures and bioactivities, represent a promising avenue for developing new antifungal therapies.
Approach:
- A comprehensive literature search was conducted across multiple databases, focusing on natural products and their derivatives with potent antifungal activity (MIC ≤ 20 μg/mL or 100 μM).
- Keywords included various classes of natural compounds (terpenoids, flavonoids, alkaloids, etc.) and their derivatives, with literature from 2001-2022 evaluated.
- The review summarizes the origin, structure, antifungal activity, mechanism of action (MoA), and structure-activity relationships (SAR) of identified compounds.
Key Points:
- 340 natural products and 34 derivatives from diverse sources (terrestrial plants, marine life, microorganisms) demonstrated significant *in vitro* and *in vivo* antifungal activity.
- Compounds exhibited potent activity against key fungal pathogens, including *Candida*, *Aspergillus*, and *Cryptococcus* species.
- Mechanisms of action included disruption of fungal cell membranes and walls, inhibition of hyphal growth and biofilms, and induction of mitochondrial dysfunction.
Conclusions:
- Natural products and their derivatives show considerable potential as lead compounds for developing new, effective, and safe antifungal agents.
- Despite incomplete understanding of their MoAs, these compounds offer novel mechanisms to overcome existing drug resistance.
- Further research into natural product-derived antifungals is crucial for addressing the growing challenge of IFIs.
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