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Antimicrobial resistance (AMR) is an emerging global threat. The World Health Organization (WHO) has predicted , classifying AMR as a leading cause of death, if no drastic measures are taken. While AMR is mainly discussed in terms of bacterial resistance, It is estimated that due to fungal infections. Over time, several strains of fungi have grown resistant to more than 1 class of antifungals, making the What is driving this increase in antifungal resistance and what can be done to stop it?

Why Do We Care ÃÞ»¨ÌÇÖ±²¥ Fungi?

Fungi are multicellular, eukaryotic organisms that are ubiquitous in the environment and body—research indicates that fungi account for ~0.1% of the human gut microbiome. Fungi can be harmless and even helpful when used as food (e.g. mushrooms, yeast, etc.) and pharmaceuticals (penicillin). However, due to their opportunistic nature, fungi can also cause infections, ranging in severity from inconvenient (yeast infection, ringworm/athletes foot, etc.) to deadly (Aspergillosis, Mucormycosis, Histoplasmosis, etc.).

Several fungi that cause invasive diseases have been classified as emerging threats by organizations, including the U.S. Centers for Disease Control and Prevention (CDC) and WHO. For example, , a pathogen of great clinical significance, causes candidiasis (especially in immunocompromised people) and has become resistant to treatments with several antifungals, including amphotericin B and fluconazole. As a result, C. auris carries a 39% mortality rate and has been classified by the CDC as an "urgent threat."

Species of fungi belonging to the Aspergillus genus represent another significant concern. A. fumigatus is a common environmental mold that has the potential to infect the lungs and respiratory tract, causing disease known as . A. fumigatus has shown a rise in azole resistance since the 1990s, resulting in treatment failures and prompting its inclusion on the CDC's "watch list."

What is Driving Antifungal Resistance?

In addition to changing environmental factors that drive evolution in fungal species (e.g., and have resulted in ), contribute to the development of antifungal resistance. Some of these include limited discovery of new antifungal agents, , overuse and over-prescription of antifungals in healthcare and failure of patients to finish the entire course of antifungal treatments when administered.

Fungal genomes are and, hence, can acquire mutations easily. However, when it comes to drug discovery, it is important to understand that very few of antifungals actually can be used as therapeutics. This is because fungi are eukaryotes, and Notably, this is .

To further complicate this issue, fungicides are regularly overused in agriculture to treat crops and livestock. As humans and animals end up , they might also inhale/ingest fungal spores from the environment, thus disrupting the microbiome by tampering with the equilibrium and potentially prompting the evolution of resistance.

Further, the tendency to and are also key drivers of resistance. Inadequate dosing may facilitate selective pressure that drives evolution of the very fungi being targeted for treatment.

Types of Therapies Available

Several existing antifungal agents currently are available for therapeutic use. Fungal drugs are categorized into 4 main classes, which may be used alone or in combination to treat various fungal diseases. Some common ‘’ antifungals are presented below, along with their mechanisms of action.

1. , such as , perturb cell structure by damaging fungal cell membranes. Resistant species include yeasts like .
2. , such as 5-fluorouracil (), obstruct nucleic acid synthesis. Resistant fungi include species of .
3. , such as , disrupt fungal cell wall synthesis. Resistant fungi include species of .
4. , such as , block metabolism by preventing ergosterol synthesis. Resistant fungi include species of .

Challenges to Antifungal Drug Development

Increased antifungal resistance leads to the At the patient level, treatment failure may translate to prolonged infection or even death. As a result, scientists are actively searching for new drug candidates, but several factors challenge antifungal drug development in ways that are unique from other antimicrobials.

1. The major problem lies with the between the human and fungal genomes, for example, it is suggested that , making it one of the most similar lower eukaryotes to humans. This means that can be due to similar enzymes and metabolic pathways.
2. It can be difficult to identify fungal species through . For example, as other Candida species, which can make infections onerous to treat and/or .
3. Several fungi exist as part of the normal microbiota and act as opportunistic pathogens, primarily in immunocompromised patients. That means that most of the time, the fungi won’t be problematic, and developing treatments for the unique conditions in which they do cause infection requires additional consideration.

What Can Be Done to Stop the Spread of Antifungal Resistance?

A collaborative approach is essential to mitigate the threat of antifungal resistance. This can be accomplished at multiple levels.

As a National Agency

CDC has several initiatives in place CDC is also and the spread of antifungal resistance at both the national and global level. Other measures include to perform testing for both infections and emergence of resistance.

As a Policymaker

Effective policies for , drug testing, and development are necessary. As antifungal resistance continues to develop, reducing the burden of fungal disease may require . Additional programs and initiatives for funding science are needed in order to enable discovery of new drugs. Encouraging and aiding in advocacy efforts and educating the public about over/underuse of antifungal drugs is also critical.

As a Medical Professional

Antifungal drugs and patients must be monitored for symptoms of resistance. If such symptoms arise, they should be documented correctly with the and . to patients may prevent emergence of resistant subpopulations of the infecting fungal strain.

As a Scientist

Creating awareness and continually is key. Most importantly, scientists must ethically and transparently work on to support the role of .

As Consumers

Consumers must be careful about how they . Follow correct dosing regimens and when visiting patients in the hospital (e.g., wash your hands). Most importantly, be sure to when prescribed, to ensure complete killing of the pathogen and prevent the rise of resistance.

While fungal infections continue to be an existing challenge in healthcare settings, antifungal resistance is an underlying threat that needs to be tackled as urgently as possible. New treatment options take time to develop. Due to increased awareness, are in place to address, and hopefully combat, antifungal (and antimicrobial) resistance.

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Understanding fungal pathogenesis is critical as scientists grow progressively concerned about shifts in fungal evolution and spread. This next article discusses how, in the face of climate change and ecological shifts, a One Health approach is key to prevention and treatment of fungal disease.