Fungicide effects on human fungal pathogens: Cross-resistance to medical drugs and beyond
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.