Are we doing enough to fight anti-fungal resistance?

Introduction to fungi

Fungi are a fascinating yet relatively untouched area of microbiology. From growing in damp forest soil to the human body, these eukaryotes (surprisingly more closely related to animals than plants!) reproduce sexually and asexually, producing hyphae (long, branching filaments) to absorb nutrients. Even in the human body, fungal infections can range from athletes' foot to severe cases of invasive pneumonia. Despite its diverse and incredibly interesting nature, only 5% of all estimated fungal species worldwide have been discovered. There is a significant lack of knowledge regarding these amazing microorganisms.

The challenge of antimicrobial resistance

Antimicrobial Resistance (AMR) is a growing concern for healthcare systems globally. AMR is the process by which microbes develop decreased sensitivity to antimicrobial drugs, meaning they can evade drug and immune response, creating the potential for superbugs (i.e. Multi-Drug Resistant Staphylococcus Aureus/MRSA). An increasing number of resistant fungal species are emerging, with more than 90% of Candida Auris strains in the US now fluconazole resistant. Microorganisms can confer resistance in various ways, such as the misuse of antimicrobial drugs and pesticides in healthcare and agriculture or random genetic evolution (secondary vs primary resistance). Biofilm formation can also contribute to this, particularly for those with inserted medical devices. This can be seen in Candidiasis, for example on inserted catheters, as can be seen in Figure 2. AMR was thought to be responsible for 1.27 million deaths globally in 2019, with an 8% increase in resistant infections in the UK from 2021-22. Global efforts regarding resistance appear to focus on antibiotic resistance, much reflective of worldwide research efforts. This leaves us wondering, are we doing enough to fight antifungal resistance?

Mechanisms of fungal resistance

Fungal infections, although typically mild, often present most severely in the immunocompromised, particularly those with cancer or who have had recent organ transplants. Invasive infections are cleared using five classes of antifungal drugs: azoles, polyenes, allylamines, flucytosine, and echinocandins, the two most common being azoles and echinocandins. Azoles aim to inhibit ergosterol synthesis, which is crucial for cell membrane stability, whilst echinocandins interfere with beta-1,3-D-glucan synthesis (a major component of fungal cell walls).

Fungi can come in two forms: mould fungi (multicellular units containing branching hyphae), and yeast fungi (unicellular with the ability to ferment carbohydrates). In yeasts, azoles target the Erg11 protein (or Cyp51A for mould fungi), which disrupts ergosterol synthesis and causes the build up of 14a-methyl sterols. In turn, this disrupts membrane activity. Azole resistance can develop through different pathways: changes in the Erg11 amino acid structure, changes in Erg11 expression, and alterations to drug efflux pathways. For Candida species, amino acid substitutions occurring at the Erg11 enzyme binding site often lead to azole resistance, whilst in Aspergillus fumigatus, changes occur at codons 54-220 in Cyp51A. Resistant Candida albicans can also overexpress Erg11, meaning a higher drug concentration is needed to combat infection. Some fungal species, such as Candida spp. confer azole resistance by utilising drug efflux systems, particularly the ABC transporter MDR1, where a gain of function mutation can lead to multidrug resistance. Loss of heterozygosity, for example, by aneuploidy, can lead to resistance if this occurs across Erg11 or MDR1 gene loci. Inhibition of the Hsp90 pathway (a component of the cellular stress response) can alleviate both azole and echinocandin resistance and regulate biofilm resistance. Hsp90 stabilises the terminal MAPK component, increasing cell wall integrity (most antifungal drugs target the fungal cell wall).

Global nature of AMR

Global schemes have emerged to combat AMR, with fungal efforts appearing to lag behind its bacterial equivalent; The WHO published its first priority bacterial pathogens list in 2017, which has been effectively used by pharmaceutical companies, researchers, and local health trusts to target bacterial species, asserting themselves as an increasing risk. WHO Fungal Priority lists didn’t emerge until 2022, which was the first global effort to establish fungal species of risk. The One Health approach, another global strategy, aims to combat AMR by emphasising collaboration between multiple sectors, increasing innovation and creating clear communication. Its main aims lay in identifying knowledge gaps, involving policymakers, creating networks and sharing data. In addition to global strategies, national ones exist. The UK government made its own five year AMR-combatting plan, implementing a OneHealth approach; Previous plans have proven successful; antimicrobial exposure was reduced by 8%, with a further 81% reduction in antibiotic sales for food-producing mammals.

It is clear AMR (particularly fungal resistance) is becoming an increasingly worrying issue. In 2019, UK deaths directly arising from drug resistant infections nearly matched those from stomach cancer, with an estimated further 35,000 deaths indirectly resulting from resistant infections. Hence, measures must be in place to contain its potential for worldwide damage. Insufficient action against AMR was predicted to have long-lasting effects like the COVID-19 pandemic every five years. Since drug-resistant fungi have the potential to cause significant burden on healthcare systems globally, what is currently being done to combat Fungal AMR?

What more can we do?

Fungal infections are the fifth leading cause of death worldwide, yet less than 1.5% of infectious disease funding goes towards research of fungal infections. This could be because fungal infections present mildly in most healthy people. However, we cannot ignore the fatal consequences for those with pre-existing illnesses or the devastating effects that could ensue if we do not make significant efforts to eliminate fungal resistance.

In its most recent five-year plan, the UK government stated its support for initiatives to increase agrochemical stewardship, particularly focussing on fungicides. The efforts outlined include establishing a pharmaceutical monitoring programme, funding research into AMR-driving chemicals, and a pilot AMR surveillance scheme. This is significant progress, however, it focuses on environmental fungal resistance, with a tendency to ignore research efforts and failing to actively address fungi in most sections.

To move forward, more efforts are needed to drive antifungal research - whether in expanding the number of antifungal classes available to patients or improving existing antifungal therapies (e.g. improvements in pharmacokinetics and efficacy). This is evidenced by the sheer number of antibiotics and respective classes compared to fungal counterparts; bacterial infections can be treated with a whopping two-fold more drug classes than their fungal equivalent. Moreover, the OneHealth approach emphasises the importance of diagnostics and testing; whilst most modern fungal testing methods are very sensitive and specific, some tests can only report positive results very late into disease progression (read more about OneHealth).  Hence, fungal diagnostic and testing approaches need to be optimised.

This all can be achieved by pushing more funding towards fungal research and development, encouraged with government spending, and an emphasis on collaboration between academia and industry. How can we relay the importance of stewardship in agriculture, or bring more treatments to the bedside without collaboration and education?

Written by Eloise Nelson

Related article: The increasing threat of anti-microbial resistance

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