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Setting New Routes for Antifungal Drug Discovery Against Pathogenic Fungi
Kleber S Freitas E Silva1, Lívia C Silva1, Relber A Gonçales1
1Laboratório de Biologia Molecular, Instituto de Ciências Biológicas, Universidade Federal de Goiás, Goiânia, Brazil.
Abstract:
Fungal diseases are life-threatening to human health and responsible for millions of deaths around the world. Fungal pathogens lead to a high number of morbidity and mortality. Current antifungal treatment comprises drugs, such as azoles, echinocandins, and polyenes and the cure is not guaranteed. In addition, such drugs are related to severe side effects and the treatment lasts for an extended period. Thus, setting new routes for the discovery of effective and safe antifungal drugs should be a priority within the health care system. The discovery of alternative and efficient antifungal drugs showing fewer side effects is time-consuming and remains a challenge. Natural products can be a source of antifungals and used in combinatorial therapy. The most important natural products are antifungal peptides, antifungal lectins, antifungal plants, and fungi secondary metabolites. Several proteins, enzymes, and metabolic pathways could be targets for the discovery of efficient inhibitor compounds and recently, heat shock proteins, calcineurin, salinomycin, the trehalose biosynthetic pathway, and the glyoxylate cycle have been investigated in several fungal species. HSP protein inhibitors and echinocandins have been shown to have a fungicidal effect against azole-resistant fungi strains. Transcriptomic and proteomic approaches have advanced antifungal drug discovery and pointed to new important specific-pathogen targets. Certain enzymes, such as those from the glyoxylate cycle, have been a target of antifungal compounds in several fungi species. Natural and synthetic compounds inhibited the activity of such enzymes and reduced the ability of fungal cells to transit from mycelium to yeast, proving to be promisor antifungal agents. Finally, computational biology has developed effective approaches, setting new routes for early antifungal drug discovery since normal approaches take several years from discovery to clinical use. Thus, the development of new antifungal strategies might reduce the therapeutic time and increase the quality of life of patients.
Insights
Discovering new antifungal drugs is crucial due to life-threatening fungal infections and current treatment limitations. Natural products and computational biology offer promising avenues for developing safer, more effective antifungal therapies.
Area of Science:
- Mycology
- Pharmacology
- Drug Discovery
Background:
- Fungal diseases cause millions of deaths globally, with current treatments (azoles, echinocandins, polyenes) often ineffective, causing severe side effects, and requiring prolonged treatment.
- The emergence of azole-resistant fungal strains necessitates urgent development of novel, safe, and effective antifungal agents.
- Natural products and novel molecular targets represent key areas for advancing antifungal drug discovery.
Purpose of the Study:
- To explore alternative and efficient antifungal drug discovery routes, focusing on natural products and novel molecular targets.
- To highlight the potential of natural products, such as antifungal peptides and lectins, in combinatorial therapy.
- To investigate the role of computational biology in accelerating the identification of new antifungal compounds.
Main Methods:
- Review of current antifungal treatments and their limitations.
- Exploration of natural product-based antifungals (peptides, lectins, plant extracts, fungal metabolites).
- Investigation of novel molecular targets including heat shock proteins (HSP), calcineurin, and metabolic pathways (trehalose biosynthesis, glyoxylate cycle).
- Application of transcriptomic, proteomic, and computational biology approaches in drug discovery.
Main Results:
- Natural products offer a rich source for discovering new antifungal agents and can be used in combinatorial therapy.
- Inhibitors of heat shock proteins (HSP) and echinocandins demonstrate fungicidal activity against azole-resistant fungi.
- Compounds targeting enzymes in the glyoxylate cycle inhibit fungal cell transition from mycelium to yeast, showing promise as antifungal agents.
- Computational biology significantly accelerates the early stages of antifungal drug discovery.
Conclusions:
- There is a critical need for novel antifungal strategies to combat life-threatening fungal infections and overcome drug resistance.
- Natural products and targeting specific fungal pathways/proteins offer promising avenues for developing safer and more effective antifungal drugs.
- Integrating advanced techniques like transcriptomics, proteomics, and computational biology is essential for efficient antifungal drug discovery and reducing patient treatment time.
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