Fungi are the single major cause of crop disease and threat to global food security, and are also increasingly important hard-to-treat human pathogens that kill more people than malaria and as many as tuberculosis and HIV. We are not overwhelmed with choices of drugs that we can use to treat plant and human infections caused by fungi, and most of the limited classes of drugs that we use today are old, and first came onto the market decades ago. But some new classes of antifungal agents that have “dual use”, as both agrotech fungicides and clinical antifungals, are coming on stream. The GW4 One Health Antimicrobial Resistance Alliance (GW4 AMR) must use its broad expertise to provide data that informs the management of these dual use agents, and devise strategies to increase their durability, by monitoring and mitigating the emergence drug resistant fungal strains.
Azole resistance as a contributor to clinical failure
The major class of antifungal agents are the azoles and triazoles. These were developed between the 1960s and 1990s as inhibitors of fungal membrane sterol formation. They have been a major dual-use class of antifungals in agriculture for crop protection and in the treatment of serious human fungal infections. In a medical context only the echinocandins (that inhibit fungal cell wall formation) have entered the market more recently, but these natural products have not thus far been found to be useful in inhibiting plant pathogens.
Surveillance studies have shown that airborne spores of the fungus Aspergillus fumigatus, are now very commonly azole resistant (Rhodes et al., 2022; Shelton et al., 2022). This organism is a common environmental fungus that exists ubiquitously in soils, composting plant matter, but is also a major cause of invasive lung disease and fungal allergy. Protection and treatment of often severely ill patients in Intensive Care Units (ITUs) is difficult enough, without the challenge of a rising tide of azole resistance that may be induced in the fields, as well as a response to medical treatment. In some settings as many at 90% of severe invasive aspergillus human infections result in death, and the burden of infection now exceeds 3,000,000 cases of chronic pulmonary aspergillosis a year (Bongomin et al., 2017). Azole resistance is a significant contributor to clinical failure (see Gow et al., 2022). The example of the dual use azoles establishes a paradigm that the exposure to a fungicide could have knock-on consequences to our ability to save patients. On the other hand, the threat to crop security and starvation imposed by fungi affects hundreds of millions of people, and fungicides are essential to prevent massive loss of essential foods around the world.
Understanding the relationship between fungicide and clinical drug failures
There is still a lot to do in understanding the relationship between the application of a fungicide in the field and downstream clinical drug failures in a hospital. It is not certain whether resistance is the direct consequence of crop protection with fungicide sprays (Barber et al.,2020), and we don’t know much about the precise environmental conditions that induce fungal resistance in field situations. Answers to these questions require research studies that often span traditional disciplinary boundaries and will require a “One Health” approach to track and assess the real risks (Verweij et al., 2022).
But new classes of antifungal drugs are like busses. You wait patiently for a long time for a new one to appear, and then several come at once! The last few years have seen four new types of antifungal emerge with new properties, chemistries or activities. Two of these (Ibrexafungerp and Oteseconazole) are new drugs that inhibit existing drug targets, but have valuable properties that show promise in augmenting the clinical armentarium. Two others (Fosmanogepix and Olorofim) are new clinical drugs that are already being used as dual use agents in agriculture (Verweij et al., 2022). The orotomoide fungicide ipflufenoquin, has a common mode-of-action with the new antifungal olorofim. They are dihydroorotate dehydrogenase (DHODH) inhibitors that affect fungal pyrimidine synthesis. This drug is effective against azole resistant Aspergillus fumigatus strains and other difficult to treat filamentous fungi. Fosmanogepix is a prodrug that targets inositol acetyltransferase Gwt1, and is essential for glycosylphosphatidylinositol (GPI)-anchors that tether essential cell wall mannoproteins in the fungal cell wall. The new fungicide aminopyrifen shares this Gwt1 target. There are, in theory, potential risks in the use of these dual-use agents in driving AMR as they are incorporated simultaneously into agriculture and medicine,
GW4 AMR – tackling the global threat of antimicrobial resistance
The GW4 Antimicrobial Resistance Alliance has expertise that spans clinical, agricultural and environmental studies of AMR and can play a major role in risk assessment and monitoring of the possible future emergence and spread of resistant mutant fungal strains that would be a potential global medical health and food security threat. Close environmental monitoring of changes in the resistance profile of environmental fungi will be important and could inform their use in field situations. It will also be useful to have greater clarity as to where and how resistance mutations arise in field situations. Alongside this evidence gathering activity, more consideration should be given to possible mitigation and prevention strategies for fungal AMR - such as the simultaneous use of combinations of inhibitors to suppress the emergence of resistant strains. Combinations of fungicides are commonly used to protect plant crops but are currently rarely used in clinical mycology.
A ‘One Health’ approach
To protect these hard won new classes of antifungals and to extend the durability of their use, a One Health approach would be helpful, and indeed essential. University alliances such as GW4, and the establishment of broad interdisciplinary research networks that transcend traditional disciplines will be important to ensure that we don’t use these drugs today and have to throw them quickly away because of fungal AMR.
Barber AE, Riedel J, Sae-Ong T, Kang K, Brabetz W, Panagiotou G, Deising HB, Kurzai O. 2020. Effects of agricultural fungicide use on Aspergillus fumigatus abundance, antifungal susceptibility, and population structure. mBio 11:e02213-20. https://doi.org/10.1128/mBio .02213-20.
Bongomin F, Gago S, Oladele RO, Denning DW. Global and Multi-National Prevalence of Fungal Diseases-Estimate Precision. J Fungi (Basel). 2017 Oct 18;3(4):57. doi: 10.3390/jof3040057. PMID: 29371573; PMCID: PMC5753159.
Gow, N.A.R., Johnson, C., Berman, J., Coste, A.T., Cuomo, C.A., Perlin, D.S., Bicanic, T., Tom Harrison, T., Wiederhold, N., Bromley, M., Chiller, T. & Edgar, K. (2022). The Importance of antimicrobial resistance in medical mycology. Nature Communications 13:5352. https://doi.org/10.1038/s41467-022-32249-5. PMID 36097014 PMCID PMC9466305
Rhodes, J., Abdolrasouli, A., Dunne, K. et al. Population genomics confirms acquisition of drug-resistant Aspergillus fumigatus infection by humans from the environment. Nat Microbiol 7, 663–674 (2022). https://doi.org/10.1038/s41564-022-01091-2
Shelton, .M.G. Collins, R., Uzzell, C.B., Alghamdi, A., Dyer, P.S., Singer, A.C. Fisher. M.C. (2022). Citizen Science Surveillance of Triazole-Resistant Aspergillus fumigatus in United Kingdom Residential Garden Soils. Applied and Environmental Microbiology 88(4) e02061-21 https://doi.org/10.1128/aem.02061-21
Verweij PE, Arendrup MC, Alastruey-Izquierdo A, Gold JAW, Lockhart SR, Chiller T, White PL. (2022). Dual use of antifungals in medicine and agriculture: How do we help prevent resistance developing in human pathogens? Drug Resist Updat. 2022 Dec;65:100885. doi: 10.1016/j.drup.2022.100885. Epub 2022 Oct 20. PMID: 36283187.
Acknowledgements: Professor Neil Gow acknowledges support of Wellcome Trust Investigator, Collaborative, Equipment, Strategic and Biomedical Resource awards (101873, 200208, 215599, 224323). NG also thanks the MRC (MR/M026663/2) and the MRC Centre for Medical Mycology (MR/N006364/2) for support. His research is also funded via the National Institute for Health and Care Research (NIHR) Exeter Biomedical Research Centre (BRC). The views expressed are those of the author and not necessarily those of the NIHR or the Department of Health and Social Care.
About the author: Professor Neil Gow is a Professor of Microbiology at the University of Exeter, and a Principle Investigator at the MRC Centre for Medical Mycology. His research speciality is the study of the biology and immunology of fungal pathogens and in particular he is interested in the structure and function of the fungal cell wall in relation to its potential target for the development of new antifungal drugs and in relation to the importance of the cell wall in initiating immune recognition. Professor Gow sits on the GW4 Alliance’s Antimicrobial Resistance Steering Group (AMR) – a ‘One Health’ AMR research consortium comprising members from the universities of Bath, Bristol, Cardiff, and Exeter.