Fig 1.
Fungicide exposure effects on Aspergillus fumigatus.
(a) Azole-susceptible and azole-resistant A. fumigatus can be identified in both fungicide-free and fungicide-containing soils and plant-based materials. There is an enrichment, however, of azole-resistant A. fumigatus in niches containing fungicides. (b) Azole-resistant A. fumigatus isolated from places holding fungicides may present some alterations compared to susceptible isolates that confer them cross-resistance with medical azoles, such as overexpression of efflux pumps and the azole-target enzyme, CYP51A, and CYP51A with a reduced azole affinity. The last 2 physiological changes are due to mutations in the gene cyp51A. The most common mutations are a pair of 34-bp sequence (in tandem) in the gene promoter (TR34), which lead to overexpression of cyp51A, together with a mutation that results in leucine replacement by histidine at position 98 (L98H) in the enzyme CYP51A, reducing the affinity of the enzyme to the azole drugs. (c) Other tandem repeat mutations combined or not with point mutations in the gene cyp51A conferring cross-resistance between environmental and medical azoles also can be detected in azole-resistant A. fumigatus isolated from fungicides-containing places. It is important to notice that the alterations represented correspond to amino acids and not in the DNA and that other tandem repeat mutations have already been observed in the clinical sets, but only TR34, TR46, and TR53 have been describing in environmental strains.
Fig 2.
Cellular alterations induced by fungicides exposure in Candida spp.
(a) Mechanisms of resistance induced by fungicides in Candida spp. Azole resistance triggered by fungicide exposure shows up-regulation of ABC multidrug transporters, such as PDH1. In addition, amino acid substitution Y132F in the erg11 gene can occur, suggesting that this selected resistance is mainly associated with increased drug efflux through ATP-dependent pumps. Sterol composition and DNA damage are also consequences of fungicide exposure. (b) Alterations in morphophysiology and virulence of Candida spp. caused by fungicides. Candida spp. exposure to fungicides showed an expanded cell size, inability to form hyphae, and significantly altered time of adhesion and decreased the metabolic activity of biofilms. ABC, ATP-binding cassette.
Fig 3.
Fungicide exposure effects on Cryptococcus spp.
(a) Exposure to fungicides can select cross-resistance to clinical azoles especially through overexpression of efflux pumps (MDR11 and AFR1) and ERG11 genes, the azole target. (b) Different fungicides also can induce important alterations in the cell morphophysiology of Cryptococcus cells that may be related to virulence.