Introduction
(Article introduction authored by ICU Editorial Team)
Invasive fungal diseases (IFDs) pose a significant global health challenge, with over 300 million severe cases and 1.5 million deaths annually. The World Health Organization (WHO) recently identified 19 priority fungal pathogens due to their impact on public health.
These fungi primarily affect immunocompromised individuals, such as those with HIV, cancer, undergoing chemotherapy, transplantation, or immunosuppressive therapy.
Limited antifungal treatments, rising drug resistance, and an increasingly vulnerable population contribute to the escalating morbidity and mortality associated with IFDs. The COVID-19 pandemic has further exacerbated this threat, making IFDs a pressing global health concern. This mini-review explores advancements and strategies in antifungal therapies to address the challenges posed by IFDs.
Conventional antifungals targets
Most serious fungal diseases are caused by Candida, Aspergillus, Cryptococcus, Pneumocystis, and various species of Mucorales [1–3]. The current antifungal agents for invasive fungal diseases (IFDs) are limited to 3 classes based on their inhibition targets. (Fig 1)
Ergosterol inhibitors
Ergosterol is a crucial component of fungal cell membranes, and its depletion through azole antifungals leads to cell death.
Azoles, inhibiting the lanosterol 14α-demethylase enzyme for ergosterol synthesis, face concerns like off-target effects and drug resistance. Recent advances include FDA-approved tetrazoles like oteseconazole with reduced off-target effects.
Opelconazole, an inhaled antifungal, shows promise in minimizing adverse effects and drug interactions. Polyenes like amphotericin B bind to ergosterol, causing membrane disintegration, but they have toxicity issues.
Encochleated amphotericin B (MAT2203) in nanoparticle form, undergoing Phase II trials, offers oral availability with reduced toxicity.
GS inhibitors
Glucan synthase (GS) plays a crucial role in fungal cell wall synthesis, particularly 1,3-β-D-glucan. GS inhibitors, like echinocandins (e.g., caspofungin, micafungin, anidulafungin), disrupt fungal cell wall formation without affecting humans.
Rezafungin, a novel echinocandin, offers once-weekly dosing for candidemia and invasive candidiasis treatment, potentially becoming the first new Candida treatment in over a decade.
Ibrexafungerp, a recently approved oral glucan synthase inhibitor, represents a novel antifungal class—the first in more than two decades.
These inhibitors provide alternatives with different modes of action compared to traditional antifungal agents like azoles and polyenes.
Other antifungal targets
Conventional antifungals are encountering resistance issues primarily due to decreased drug-target interaction. Genetic changes, especially mutations in genes like those encoding β-glucan synthase, lead to antifungal drug resistance.
To address this, new antifungal targets are being explored, including glycosylphosphatidylinositol (GPI), chitin synthase, histone deacetylase, mitochondrial-related pathways, and pyrimidine synthase.
Olorofim, a pyrimidine synthase inhibitor, recently received FDA orphan drug designation for treating coccidioidomycosis and scedosporiosis. Progress has also been made in inhibiting fungal biofilms, with promising compounds in clinical trials. Additionally, insights into fungal virulence pathways offer potential targets for future antifungal drug development.
Antifungal immunotherapy in invasive fungal infection
The toxicity and rising drug resistance linked to traditional fungal chemotherapies necessitate urgent exploration of new antifungal therapies. Immunotherapies, inspired by successful cancer treatments targeting PD-1 and CTLA-4 pathways, offer a promising alternative for invasive fungal diseases (IFDs).
Unlike direct-drug approaches, antifungal immunotherapy stimulates the immune system to combat fungal infections, potentially providing a more specific and adaptable solution. Advances in fungal immunology research have paved the way for various experimental antifungal immunotherapies, including vaccines, immunomodulatory drugs, monoclonal antibodies, and adoptive T-cell therapy.
Notable developments include the effectiveness of the anti-Adh1 monoclonal antibody (Ca37) against Candida albicans and the Phase II trial of the fungal immunotherapeutic vaccine (NDV-3A) for recurrent vulvovaginal candidiasis.
Recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF) has received approval as an adjuvant therapy for IFDs.
Additionally, D-CAR T cells and antimicrobial peptides (AMPs) like HIF-1α and LL-37 show promise in reducing fungal burden. While these immunotherapies hold great potential, further research is essential to validate their safety and effectiveness in human patients, particularly those with compromised immune systems.
Discussion
Developing antifungal therapies poses greater challenges than antibacterial drugs due to evolutionary similarities between fungal and mammalian cells.
Antifungals can target specific fungal or shared mammalian structures with differences. Understanding resistance mechanisms and fungal pathogenicity is crucial for novel antifungal target identification.
Strategies include repurposing drugs like FK506 and cyclosporin A, exploring combination therapy for enhanced efficacy, utilizing antifungal target gene-directed genome mining for natural product discovery, leveraging innate host resistance, and employing bioengineering for diverse antifungal agents.
Advanced drug discovery technologies and research on fungal pathogen-host interactions hold promise for emerging antifungal therapies with improved safety and reduced drug resistance, especially for invasive fungal diseases.
Source: Zhang, Zhuan, Gerald F. Bills, and Zhiqiang An. “Advances in the treatment of invasive fungal disease.” PLoS Pathogens 19.5 (2023): e1011322.
