Tackling the emerging threat of antifungal resistance to human health

Abstract

Invasive fungal infections pose an important threat to public health and are an under-recognized component of antimicrobial resistance, an emerging crisis worldwide. Across a period of profound global environmental change and expanding at-risk populations, human-infecting pathogenic fungi are evolving resistance to all licensed systemic antifungal drugs. In this Review, we highlight the main mechanisms of antifungal resistance and explore the similarities and differences between bacterial and fungal resistance to antimicrobial control. We discuss the research and innovation topics that are needed for risk reduction strategies aimed at minimizing the emergence of resistance in pathogenic fungi. These topics include links between the environment and One Health, surveillance, diagnostics, routes of transmission, novel therapeutics and methods to mitigate hotspots for fungal adaptation. We emphasize the global efforts required to steward our existing antifungal armamentarium, and to direct the research and development of future therapies and interventions.

Fig. 1. Major routes to acquiring antifungal drug resistance and/or tolerance in key invasive human fungal pathogens.

Routes to acquiring antifungal drug resistance and/or tolerance vary depending on the mode of action (MOA). a | Azole drug resistance is primarily due to increased efflux of the drug from the fungal cell (particularly in Candida spp.) and modifications to the sterol biosynthesis pathway caused by point mutations and promoter insertions in CYP51A (Aspergillus fumigatus). In other fungal species, such as Cryptococcus neoformans, overexpression of the drug target and efflux pumps caused by chromosomal aneuploidy and hypermutation is common. b | Polyenes alter cell membrane permeability by forming a complex with ergosterol, and resistance is caused by loss-of-function mutations in ergosterol biosynthesis genes (particularly in Aspergillus and Candida spp.). In Candida albicans in particular, double loss of ERG3 confers resistance. However, drug tolerance is common, via upregulation of ERG5, ERG6 and ERG25 in C. albicans. c | Cell membrane stress can also impact regulators of HSP90, conferring drug tolerance. Echinocandins inhibit 1,3-β-d-glucan synthase (FKS1), and mutations in this gene cause resistance in Candida and Fusarium spp. Echinocandin exposure can also lead to cell wall stress through inhibition of β-glucan synthase, with indirect downstream activation of Ca²⁺/calcineurin or HSP90/mTOR pathways, which are involved in drug tolerance. d | Pyrimidine analogues such as 5-flucytosine inhibit DNA and RNA synthesis. Resistance can arise via point mutations in the target gene FCY1, and is common in Candida spp. Hypermutation in Cryptococcus spp. is also known to cause resistance to this drug class. TR, tandem repeat.

Fig. 2. Emerging antifungal resistance and environment–One Health drivers.

Fungi in the environment are exposed to broad-spectrum classes of antifungals that are also utilized as frontline antifungal treatments in the clinic. Ecological hotspots occur that can act as amplifiers of resistant genotypes. One example is green waste stockpiling and composting. Humans with invasive fungal diseases (IFDs) may also transmit resistant genotypes (for instance in nosocomial outbreaks); however, the extent to which humans and other animals contribute to the presence of antifungal resistance in the environment remains unknown. Multiple extrinsic factors exist that are expected to influence the incidence of antifungal resistance. These include changing patterns of fungicide use in the environment and in waste management; changing at-risk human host groups including viral infections such as COVID-19; changing climates that may alter the geographical range of fungi and adaptive landscape for resistance as well as providing novel routes for infection (for example, natural disasters); changing biotic interactions that may include xenobiotic chemicals that are analogues to antifungals; and changing virulence of the fungi themselves owing to intrinsic genetic change or synergies with combinations of the above drivers.

Fig. 3. Resistance detection, tracking and surveillance.

Fungal samples can be acquired from the clinic or environment, including engaging with the public as ‘citizen scientists’. Traditional, established microbiology methods can culture and select isolates from these samples, ready for extraction of genomic DNA. These DNA fragments are used to generate a sequencing library for whole-genome sequencing (WGS). There are many sequencing platforms available, generating both long-read and short-read sequence data. Raw sequence data need to be quality controlled prior to mapping against a reference genome, either locally or using cloud computing. Calling high-confidence single-nucleotide polymorphisms (SNPs) can help infer alleles associated with drug resistance and their evolutionary histories. Phylodynamic inference and building interactive online portals (such as Nextstrain or Microreact) that are available to researchers and clinicians alike enable tracing of transmission events.

Fig. 4. Interventions for invasive fungal infections within the landscape of antifungal resistance.

Synoptic integrated One Health understanding is necessary to understand not only the complex multifactorial pathways that lead to the emergence of resistance across the fungal kingdom but also potential interventions to mitigate the rate of emergence. a | Complex biotic and abiotic interactions lead to occurrence of evolutionary hotspots for antimicrobial resistance (AMR) development in environmental opportunistic fungi requiring targeted interventions in the environment. b,c | Patient exposures to environmental AMR require enhanced methods of detection with more focus on key fungal life-history factors (part b), and new and emerging drug-resistant fungal pathogens that have the potential for global nosocomial carriage and outbreaks in health-care settings require transnational surveillance (part c). A cross-cutting theme is the need for industry to separate development and use of agricultural fungicides from those antifungals that are used in the clinic to develop treatments that are resilient to the evolutionary forces at play in parts a–c. GLASS, Global Antimicrobial Resistance Surveillance System; WHO, World Health Organization.