Programmed cell death in human pathogenic fungi – a possible therapeutic target

ABSTRACT

Introduction: Diseases caused by pathogenic fungi are increasing because of antibiotic overuse, the rise of immunosuppressive therapies, and climate change. The limited variety of antimycotics and the rapid adaptation of pathogenic fungi to antifungal agents serve to exacerbate this issue. Unfortunately, about 1.6 million people are killed by fungal infections annually.

Areas covered: The discovery of the small antimicrobial proteins produced by microorganisms, animals, humans, and plants will hopefully overcome challenges in the treatment of fungal infections. These small proteins are highly stable and any resistance to them rarely evolves; therefore, they are potentially good candidates for the treatment and prevention of infections caused by pathogenic fungi. Some of these proteins target the programmed cell death machinery of pathogenic fungi; this is potentially a novel approach in antimycotic therapies. In this review, we highlight the elements of apoptosis in human pathogenic fungi and related model organisms and discuss the possible therapeutic potential of the apoptosis-inducing, small, antifungal proteins.

Expert opinion: Small antimicrobial proteins may establish a new class of antimycotics in the future. The rarity of resistance and their synergistic effects with other frequently used antifungal agents may help pave the way for their use in the clinic.

KEYWORDS:

• Human pathogenic fungi
• programmed cell death
• small antifungal proteins
• heterologous expression

Article Highlights

• Despite several antifungal agents, like azoles, 5-fluorocytosine, polyenes, allylamines, and echinocandins, used in the treatment of fungal infections still cause challenges and unfortunately more than 1 million people still die from fungal diseases annually.

• The small antimicrobial proteins with its outstanding stability and rare development of resistance are promising novel antimycotic candidates.

• These antifungal proteins do not show toxicity to mammalian including human cells, therefore selectively target human pathogenic fungi.

• Some of the antifungal proteins induce programmed cell death in sensitive fungi instead of simply necrotizing sensitive fungal cells through disrupting their plasma membrane.

• Further research is needed to shed light on the cellular targets of these proteins, which would make future rational drug design possible.

• Promising antifungal protein candidates should be introduced into clinical trials and eventually into human therapy.

This box summarizes key points contained in the article.

Acknowledgments

The authors are indebted to Dr. Mattia Joan Plubell for editing the English of the paper.

Declaration of interest

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose

Additional information

Funding

This work was supported by the European Union and the European Social Fund through the EFOP-3.6.1-16-2016- 00022 and GINOP-2.3.2-15-2016-0044 projects and by the Higher Education Institutional Excellence Programme of the Ministry of Human Capacities in Hungary, within the framework of the Biotechnology Thematic Programme of the University of Debrecen, Hungary.