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Fungi are known to utilize transcriptional regulation of genes that encode efflux transporters to detoxify xenobiotics; however, to date it is unknown how fungi transcriptionally regulate and coordinate different phases of detoxification system (phase I, modification; phase II, conjugation; and phase III, secretion). Here we present evidence of an evolutionary convergence between the fungal and mammalian lineages, whereby xenobiotic detoxification genes (phase I coding for cytochrome P450 monooxygenases [CYP450s] and phase III coding for ATP-binding cassette [ABC] efflux transporters) are transcriptionally regulated by structurally unrelated proteins. Following next-generation RNA sequencing (RNA-seq) analyses of a filamentous fungus, Sclerotinia homoeocarpa, the causal agent of dollar spot on turfgrasses, a multidrug resistant (MDR) field strain was found to overexpress phase I and III genes, coding for CYP450s and ABC transporters for xenobiotic detoxification. Furthermore, there was confirmation of a gain-of-function mutation of the fungus-specific transcription factor S. homoeocarpa XDR1 (ShXDR1), which is responsible for constitutive and induced overexpression of the phase I and III genes, resulting in resistance to multiple classes of fungicidal chemicals. This fungal pathogen detoxifies xenobiotics through coordinated transcriptional control of CYP450s, biotransforming xenobiotics with different substrate specificities and ABC transporters, excreting a broad spectrum of xenobiotics or biotransformed metabolites. A Botrytis cinerea strain harboring the mutated ShXDR1 showed increased expression of phase I (BcCYP65) and III (BcatrD) genes, resulting in resistance to fungicides. This indicates the regulatory system is conserved in filamentous fungi. This molecular genetic mechanism for xenobiotic detoxification in fungi holds potential for facilitating discovery of new antifungal drugs and further studies of convergent and divergent evolution of xenobiotic detoxification in eukaryote lineages.
Sclerotinia homoeocarpa (F. T. Bennett) is one of the most economically important pathogens on high-amenity cool-season turfgrasses, where it causes dollar spot. To understand the genetic mechanisms of fungicide resistance, which has become highly prevalent, the whole genomes of two isolates with varied resistance levels to fungicides were sequenced.
Cytochrome P450s have been shown to play a vital role in the xenobiotic detoxification system of Sclerotinia homoeocarpa, the causal agent of the turfgrass disease dollar spot. A previous study indicated that three CYP450s were validated to play a functional role in resistance against different fungicide classes including propiconazole and plant growth regulator, flurprimidol. In this study, we present these CYP450s possess the capability to modify the multi-site mode of action fungicide chlorothalonil. Chlorothalonil is an extensively used contact fungicide and has been shown to persist in soils. High Performance Liquid Chromatography (HPLC) indicated faster rates of chlorothalonil biotransformation by CYP561 and CYP65 overexpression strains when compared to the wild-type and CYP68 overexpression strain. Our GC-MS results show that the primary transformation intermediate found in soils, 4-hydroxy-2,5,6 trichloro-isophthalonitrile is produced by CYP450s' metabolism. These findings suggest fungal CYP450s can biotransform chlorothalonil for biodegradation or detoxification.
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