Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2023 Dec;21(12):818-832.
doi: 10.1038/s41579-023-00960-9. Epub 2023 Aug 30.

The rapid emergence of antifungal-resistant human-pathogenic fungi

Shawn R Lockhart  1 , Anuradha Chowdhary  2   3 , Jeremy A W Gold  4
Affiliations
Review

The rapid emergence of antifungal-resistant human-pathogenic fungi

Shawn R Lockhart et al. Nat Rev Microbiol. 2023 Dec.

Abstract

During recent decades, the emergence of pathogenic fungi has posed an increasing public health threat, particularly given the limited number of antifungal drugs available to treat invasive infections. In this Review, we discuss the global emergence and spread of three emerging antifungal-resistant fungi: Candida auris, driven by global health-care transmission and possibly facilitated by climate change; azole-resistant Aspergillus fumigatus, driven by the selection facilitated by azole fungicide use in agricultural and other settings; and Trichophyton indotineae, driven by the under-regulated use of over-the-counter high-potency corticosteroid-containing antifungal creams. The diversity of the fungi themselves and the drivers of their emergence make it clear that we cannot predict what might emerge next. Therefore, vigilance is critical to monitoring fungal emergence, as well as the rise in overall antifungal resistance.

PubMed Disclaimer

Conflict of interest statement

Competing Interests: The authors declare no competing interests.

Figures

Figure 1.
Figure 1.. Global disbursement of the three emerging fungi Candida auris, azole-resistant Aspergillus fumigatus and Trichophyton indotineae.
The presence of any of the organisms in a country does not mean they are ubiquitous there, and in some cases may be represented by a single isolate. a). Map of countries that have reported cases of Candida auris. b). Map of countries that have reported azole-resistant Aspergillus fumigatus containing the TR34/L98H or TR46/Y121F/T289A mutation in patients. c) Map of countries that have reported azole-resistant A. fumigatus containing the TR34/L98H or TR46/Y121F/T289A mutation in the environment. D) Map of countries where Trichophyton indotineae has been identified from patients or the country where the infection was most likely acquired.
Figure 1.
Figure 1.. Global disbursement of the three emerging fungi Candida auris, azole-resistant Aspergillus fumigatus and Trichophyton indotineae.
The presence of any of the organisms in a country does not mean they are ubiquitous there, and in some cases may be represented by a single isolate. a). Map of countries that have reported cases of Candida auris. b). Map of countries that have reported azole-resistant Aspergillus fumigatus containing the TR34/L98H or TR46/Y121F/T289A mutation in patients. c) Map of countries that have reported azole-resistant A. fumigatus containing the TR34/L98H or TR46/Y121F/T289A mutation in the environment. D) Map of countries where Trichophyton indotineae has been identified from patients or the country where the infection was most likely acquired.
Figure 2.
Figure 2.
The more common mechanisms of acquired antifungal resistance of Candida auris. One of the most remarkable aspects of C. auris is the number of different mechanisms of acquired antifungal resistance that have been identified. For the azoles, especially fluconazole, these include mutations in the target enzyme lanosterol demethylase (ERG11), mutations in transcription factors such as TAC1B that lead to the over-expression of efflux pumps, and changes in ploidy that lead to overexpression of ERG11 and target site dilution. For the echinocandins, the predominant mechanism of resistance is a change in the amino acid sequence at the target site hotspot in Fks1p the mechanism that is conserved across Candida species. For amphotericin B, a specific amino acid change in Ergp6 that alters membrane sterol composition has been identified, but other, as yet unidentified, mechanism that prevent ergosterol sequestration have been identified phenotypically but not molecularly.
Figure 3.
Figure 3.
Diagram of possible routes of acquisition of antifungal resistant Aspergillus fumigatus.
Figure 4.
Figure 4.
Mechanisms of acquired resistance of azole-resistant Aspergillus fumigatus. Azole resistance in A. fumigatus appeared almost as soon as azoles became available. Approximately 30% of isolates have no identified mechanism of resistance, but the other 70% have changes either in the azole target enzyme lanosterol demethylase (CYP51A), or in HMG1, the gene encoding hydroxymethylglutaryl-CoA reductase, a rate-limiting enzyme in the ergosterol pathway. Some target site mutations, such as those at amino acids G54, G138, P216, M220 and G448, are associated predominantly with acquired resistance following long-term azole treatment. There is a unique set of targets, TR34/L98H (TR34) and TR46/Y121F/T289A (TR46) that are specifically associated with environmental acquisition of resistance due to exposure to agricultural fungicides. These mutations consist of both a duplication in the 5’ untranslated region that causes increased transcription and a single or double amino acid change in the target binding site. The TR34 mutation leads to pan-azole resistance while the TR46 mutation is specific for voriconazole resistance.
Figure 5.
Figure 5.
Mechanisms of acquired resistance of Trichophyton indotineae. T. indotineae is a newly emerging species so our current knowledge of the mechanisms of resistance is limited. Resistance to terbinafine is caused by specific mutations in the target enzyme, squalene epoxidase, which may also lead to azole resistance as it is a component of the ergosterol pathway. Azole resistance has been linked to changes in the target enzyme lanosterol demethylase (CYP51B) either through amino acid mutation, changes in ploidy, or mutations in transcription factors that result in overexpression.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Rigling D & Prospero S Cryphonectria parasitica, the causal agent of chestnut blight: invasion history, population biology and disease control. Mol Plant Pathol 19, 7–20, doi:10.1111/mpp.12542 (2018). - DOI - PMC - PubMed
    1. Dita M, Barquero M, Heck D, Mizubuti ESG & Staver CP Fusarium Wilt of Banana: Current Knowledge on Epidemiology and Research Needs Toward Sustainable Disease Management. Front Plant Sci 9, 1468, doi:10.3389/fpls.2018.01468 (2018). - DOI - PMC - PubMed
    1. Fisher MC & Garner TWJ Chytrid fungi and global amphibian declines. Nat Rev Microbiol 18, 332–343, doi:10.1038/s41579-020-0335-x (2020). - DOI - PubMed
    1. Hoyt JR, Kilpatrick AM & Langwig KE Ecology and impacts of white-nose syndrome on bats. Nat Rev Microbiol 19, 196–210, doi:10.1038/s41579-020-00493-5 (2021). - DOI - PubMed
    1. Martin-Urdiroz M, Oses-Ruiz M, Ryder LS & Talbot NJ Investigating the biology of plant infection by the rice blast fungus Magnaporthe oryzae. Fungal Genet Biol 90, 61–68, doi:10.1016/j.fgb.2015.12.009 (2016). - DOI - PubMed

LinkOut - more resources