Abstract
Fungal infections are underestimated threats that affect over 1 billion people, and Candida spp., Cryptococcus spp., and Aspergillus spp. are the 3 most fatal fungi. The treatment of these infections is performed with a limited arsenal of antifungal drugs, and the class of the azoles is the most used. Although these drugs present low toxicity for the host, there is an emergence of therapeutic failure due to azole resistance. Drug resistance normally develops in patients undergoing azole long-term therapy, when the fungus in contact with the drug can adapt and survive. Conversely, several reports have been showing that resistant isolates are also recovered from patients with no prior history of azole therapy, suggesting that other routes might be driving antifungal resistance. Intriguingly, antifungal resistance also happens in the environment since resistant strains have been isolated from plant materials, soil, decomposing matter, and compost, where important human fungal pathogens live. As the resistant fungi can be isolated from the environment, in places where agrochemicals are extensively used in agriculture and wood industry, the hypothesis that fungicides could be driving and selecting resistance mechanism in nature, before the contact of the fungus with the host, has gained more attention. The effects of fungicide exposure on fungal resistance have been extensively studied in Aspergillus fumigatus and less investigated in other human fungal pathogens. Here, we discuss not only classic and recent studies showing that environmental azole exposure selects cross-resistance to medical azoles in A. fumigatus, but also how this phenomenon affects Candida and Cryptococcus, other 2 important human fungal pathogens found in the environment. We also examine data showing that fungicide exposure can select relevant changes in the morphophysiology and virulence of those pathogens, suggesting that its effect goes beyond the cross-resistance.
Highlights
Candida spp., Cryptococcus spp., and Aspergillus spp. are among the 3 most lethal human pathogenic fungi [1] as they can cause severe systemic infections, which may be fatal even when treated [2]
Microbiological resistance is defined as the inability of an antifungal to kill or inhibit the fungal growth in vitro [6,12,13] and can be divided into 2 classes: (i) primary or intrinsic resistance, when a microorganism is naturally resistant to a drug, without previous exposure; and (ii) secondary resistance, when resistance mutations evolve in the population and are selected upon exposure to an antifungal [6]
Many epidemiological and experimental data corroborate the theory that the demethylase inhibitors (DMIs) used in the wood and textile industries, and especially those employed in agriculture, may select azole resistance in A. fumigatus in the environment [29,33,46,73,74] (Fig 1A)
Summary
Candida spp., Cryptococcus spp., and Aspergillus spp. are among the 3 most lethal human pathogenic fungi [1] as they can cause severe systemic infections, which may be fatal even when treated [2]. Antifungal resistance happens in the environment since resistant strains have been isolated from plant material, soil, decomposing matter, and compost [19,20,21,22,23,24,25,26,27] This fact raises an important question: How does resistance to azoles arise in environmental isolates?. Since certain potential human pathogens can be isolated from plant material and soil, the most accepted hypothesis is that agrochemicals, especially 14α-demethylase inhibitors (DMIs), operate as a selection pressure for the emergence of resistant strains in the environment (fungicide-driven drug resistance route) [26,31]. We discuss how this phenomenon can affect Candida and Cryptococcus, other 2 important human fungal pathogens found in the environment
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