Antifungal resistance: an overlooked killer

By Samrah Siddiqi 

The advancement of modern medicine has emerged with many challenges. The misuse and overuse of antibiotics is a familiar concept to all. Antimicrobial resistance (AMR) is a term which has been in the limelight for the past several decades, with growing focus on antibacterial resistance. However, problems associated with antifungal resistance, which is equally as deadly, have often been overlooked (Helen Albert, 20202). In 2018, the UK government put aside £20 million out of £30 million to fund antibiotic resistance related research and development. A mere £5 million was used to fund an AMR research group looking at the impact of antimicrobial resistance in agriculture and the environment (GOV.UK, 2020). Life threatening systemic fungal infections are on the rise, with mortality rates reported to have risen from 35% to 80% with current standard of care. Fungi have clearly developed the ability to win the battle against the drugs designed to kill them, rendering the antifungal drugs ineffective (Centers for Disease Control and Prevention, 2020). As fungi share the eukaryotic domain with humans, similarities make it difficult to develop new nontoxic antifungal drugs, an issue less prevalent with other microbes such as bacteria which are less closely related to humans (Helen Albert, 2020). With opportunistic fungal infections becoming an increasing threat globally, especially with the rising number of immunocompromised COVID-19 patients, funding for the development of promising new drugs is imperative. 

Fungi exist in two forms: yeasts and moulds. Asexual reproduction of fungi involves production of microscopic spores (Biology Libre Texts, 2020).  These spores spread in soil and air, enabling contact with humans via inhalation or via contact with skin. As a result, fungal infections often start in the lungs or on the skin (S.G. Revankar, 2020). It is fairly common for mild fungal infections to take place, e.g. under the nails. However, humans have developed a somewhat natural resistance to these types of infections. Severe fungal infections which require therapeutic intervention arise when patients are immunocompromised due to previous diseases or use of immunosuppressants. Additionally, introduction of foreign material into the body, for example during surgery, can trigger severe fungal infections (S.G. Revankar, 2020). These opportunistic infections include aspergillosis, candidiasis and mucormycosis; all caused by entry of different types of fungi (Aspergillus, Candida and moulds) into various body parts (S.G Revankar, 2020).  

The only readily available treatment for fungal infections at the moment is antifungal drugs.  

Improper use of these drugs, in addition to the longevity of usage (patients have to be treated for several months with the same drug), has led to resistance among fungal species (Centers for Disease Control and Prevention, 2020).  Alternatively, some fungal species are naturally resistant to certain types of antifungal drugs (Centers for Disease Control and Prevention, 2020). This antifungal resistance poses a great threat to suffering patients as their choice of treatment is already limited with only three types of antifungal drugs available on the market: polyenes, azoles, and echinocandins (Helen Albert, 2020).  These drugs differ in their sites of action and targets. Polyenes and azoles work by altering the permeability of the fungal cell membrane which creates pores facilitating leakage of cellular contents, ultimately resulting in cellular apoptosis (Med Made Sirius-ly easy!, 2019). The function of echinocandins is to block b-glucan synthesis – an essential fungal cell wall component (Med Made Sirius-ly easy!, 2019). Using these different mechanisms of action, antifungal drugs are able to stop the spread of these deadly killers – however, they do each have their own limitations, reducing their applicability. The most commonly used polyene is a drug called amphotericin B. Resulting approval of this drug in the 1950s drastically improved patient’s survival prospects, however, recent developments have shown that the drug is associated with serious side effects such as kidney problems (Helen Albert, 2020). Azoles have been regarded the most successful antifungal drug to date after approval in the 1980s. Nonetheless, they come with their own problems such as their ability to inhibit cytochrome p450 – a detoxifying enzyme essential for maintaining normal blood homeostasis (Helen Albert, 2020). Echinocandin use is not associated with internal problems of the body, however, the once-a-day dosage required for patients is considered a liability – especially when patients require month-long treatments at any given time (Helen Albert, 2020). 

Examples of resistant fungi include Candida Auris, which can develop resistance to all three drug types, and Aspergillus, which is resistant to azole drug fluconazole (Centers for Disease Control and Prevention, 2020). Excessive use of azoles in agriculture has accelerated fungal resistance. This is a particularly prevalent issue in the Netherlands – home to many flower farms where the common fungus Aspergillus residesAspergillus has the ability to cause severe damage to immunocompromised individuals. Farmers in the Netherlands spray their fields continuously with low concentrations of azoles and as a result, Netherlands has one of the highest rates of azole-resistant invasive aspergillosis in the world (Helen Albert, 2020). Fungal resistance is particularly concerning for patients with serious infections of the blood, heart, brain, eyes and other parts of the body as it is difficult to eradicate the infections with such limited treatment options available (Centers for Disease Control and Prevention, 2020). This highlights the need for new drugs in the pipeline. 

The future of the antifungal space is very exciting. The COVID-19 pandemic this year has helped to highlight the importance of this area of drug development. Four biotech companies are currently testing novel antifungals in the phase II and phase III trials stage; fosmanogepix from US biotech Amplyx, rezafungin from California-based Cidara, olorofim from UK biotech F2G and ibrexafungerp from New Jersey-based Scynexis (Helen Albert, 2020). Rezafungin and ibrexafungerp are both more advanced in phase III trials, with olorofilm and fosmanogepix close behind in phase II trials (Helen Albert, 2020). Rezafungin is the newest addition to the echinocandin class (Helen Albert, 2020). It is an intravenous drug which will have to be administered once a week at a high dose as opposed to the current methods of treatment which are administered daily (Helen Albert, 2020). It is able to be given at a high dose because it doesn’t break down and thus does not induce unwanted liver toxicity (Helen Albert, 2020). Ibrexafungerp is the most advanced novel antifungal drug currently being developed (Helen Albert, 2020). It will be orally administered which is advantageous as patients will be allowed to be discharged whilst taking the treatment (Helen Albert, 2020). Olorofilm is the first drug in the orotomide drug class (Helen Albert, 2020).  It halts fungal growth by inhibiting pyrimidine synthesis and targeting fungal enzyme dihydroorotate dehydrogenase (Helen Albert, 2020). Fosmanogepix also targets another enzyme specific to fungi called Gwt1 (Helen Albert, 2020). This specificity ensures that the drug does not cause any adverse effects in humans (Helen Albert, 2020). Fungi are no longer able to evade the immune system after fosmanogepix is given as a treatment (Helen Albert, 2020). In trials to date, these four drugs have shown broad efficacy and promising data. However, drug development and clinical trials are time consuming processes but with the perseverance of these four companies there is reason to be hopeful for the future of this sector.  

References:

Albert H. (2020) Why New Antifungals Are Desperately NeededAvailable from: https://www-labiotech-eu.cdn.ampproject.org/c/s/www.labiotech.eu/medical/new-antifungals-development/amp/ [Accessed 19th September 2020] 

Biology Libre Texts. (2020) Fungi Reproduction. Available from: https://bio.libretexts.org/Bookshelves/Introductory_and_General_Biology/Book%3A_General_Biology_(Boundless)/24%3A_Fungi/24.1%3A_Characteristics_of_Fungi/24.1C%3A_Fungi_Reproduction [Accessed 19th September 2020] 

Centers for Disease Control and Prevention. (2020) Antifungal Resistance. Available from: https://www.cdc.gov/fungal/antifungal-resistance.html [Accessed 19th September 2020] 

GOV.UK. (2018) £30 million of funding to tackle antimicrobial resistanceAvailable from: https://www.gov.uk/government/news/30-million-of-funding-to-tackle-antimicrobial-resistance [Accessed 19th September 2020] 

Med Made Sirius-ly easy! (2019) Pharmacology-Antifungal drugs MADE EASY! Available from: https://www.youtube.com/watch?v=R-8KN9rIwDA&t=199s [Accessed 19th September 2020]  

Revankar S.G. (2019) Overview of Fungal Infections. Available from: https://www.msdmanuals.com/home/infections/fungal-infections/overview-of-fungal-infections [Accessed 19th September 2020] 

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