Rising Resistance to Anti-Fungal Drugs: A Review

The Impact of Fungal Pathogens

A recent review published in *Science* highlights a concerning increase in resistance to anti-fungal drugs used in agriculture, animal care, and human health. Fungal pathogens significantly threaten our food supply and well-being, contributing to an estimated 20% loss in crop yields before harvest and approximately 10% after harvest. In terms of human health, the impact of global fungal diseases is comparable to that of tuberculosis and HIV.

Challenges Posed by Pathogenic Fungi

Despite rigorous measures to control the spread of fungal pathogens, research reveals that resistance among these organisms is alarmingly prevalent. This resistance is largely attributed to the adaptable nature of the fungal genome, which can quickly respond to the pressures exerted by anti-fungal treatments. Additionally, monoculture farming practices create ideal conditions for these pathogens to flourish. Preventive anti-fungal treatments in human medicine can also lead to resistance, similar to antibiotic resistance observed in bacteria.

Limited Anti-Fungal Strategies

Current Approaches to Combat Fungi

Decades of research have yielded a limited range of strategies to combat fungal pathogens, categorized into three primary mechanisms:

1. Disruption of the structural integrity of the fungal cell wall.
2. Interference in the metabolism of key components necessary for maintaining and synthesizing the fungal cell wall, including ergosterol and glucans.
3. Inhibition of pyrimidine biosynthesis, crucial for DNA replication, thereby hindering the proliferation of fungal pathogens.

Factors Contributing to Resistance

The extensive use of pesticides can weaken plants’ natural defenses, facilitating the adaptation of fungal pathogens based on the predictable action modes of classical anti-fungal drugs. In humans, treatments for HIV and other medical interventions that suppress the immune system can allow fungi to evade detection and cause opportunistic infections. The global movement of people and goods further enables the spread of fungal diseases, as seen with *Candida auris*, which transitioned from being confined to Japan to causing hospital-acquired infections worldwide.

The indiscriminate use of anti-fungal drugs as preventive measures may also lead to the pre-sensitization of pathogens, allowing them to evolve resistance mechanisms. This phenomenon has been documented with *Candida glabrata*, which has developed resistance due to repeated exposure to azole antifungals. Resistance is also a growing concern among plant pathogens, with over 90 types exhibiting resistance to benzimidazole drugs and at least 17 new plant pathogens identified as resistant to succinate dehydrogenase inhibitors within the past decade.

Molecular Mechanisms of Anti-Fungal Resistance

How Fungal Pathogens Adapt

Fungal pathogens employ various mechanisms to develop resistance. One prevalent method is the emergence of novel mutations that alter the targets of anti-fungal drugs. These mutations are genetic changes that modify the coding region of DNA, resulting in altered protein sequences that hinder drug interaction. For example, a single amino-acid mutation in cytochrome b has been linked to resistance in at least 20 plant pathogen species.

Some fungi can actively expel anti-fungal drugs using efflux pumps, while others utilize Hsp90 chaperone proteins to mitigate the stress caused by these drugs. This protein helps fungi manage drug-induced toxicity by activating stress response pathways and assisting in the proper folding of key proteins, enabling them to survive anti-fungal treatments.

Strategies to Combat Anti-Fungal Resistance

Exploring New Approaches

Addressing the growing issue of anti-fungal resistance requires a multifaceted approach. Key strategies include:

1. Increasing research efforts to develop new classes of anti-fungal drugs that operate through novel mechanisms. Several new anti-fungal agents are currently in phase 1 and 2 clinical trials.
2. Utilizing combinations of multiple anti-fungal drugs with distinct mechanisms to enhance efficacy.
3. Developing tailored molecular diagnostic methods to target anti-fungal treatments more precisely, reducing the likelihood of broad-spectrum resistance.

While various strategies exist to combat anti-fungal resistance, no single approach can effectively address the diverse mechanisms at play. Continued research is essential to mitigate the losses caused by fungal pathogens.

Conclusion

The fight against anti-fungal resistance is crucial for safeguarding global health and food security. Ongoing research and innovative strategies are necessary to counteract the rising threat posed by these resilient pathogens.

Written by Vinayak Khattar, Ph.D., M.B.A.

Reference

Fisher M, Hawkins N, Sanglard D, Gurr S. Worldwide emergence of resistance to antifungal drugs challenges human health and food security. *Science*. 2018;360(6390):739-742.