Natural Products as Antifungal Agents against Invasive Fungi

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 com-monly used chemical drugs. Therefore, the search for alternative drugs with high efficacy, low re-sistance 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. Objective: 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, macro-lide, peptide, tetramic acid glycoside, polyene, polyketide, bithiazole, natural product, and deriva-tives. 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 Can-dida 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.