N6-methyloxyadenine-mediated detoxification and ferroptosis confer a trade-off between multi-fungicide resistance and fitness

• Published in: mBio Vol. 15; no. 3; p. e0317723
• Main Authors: Zhang, Borui, Wang, Zhiwen, Zhang, Sicong, Zhong, Shan, Sun, Ye, Liu, Xili
• Format: Journal Article
• Language: English
• Published: United States American Society for Microbiology 13.03.2024
• Subjects: detoxification; DNA N6-methyloxyadenine; ferroptosis; fitness penalty; Microbial Genetics; Research Article; DNA N6-methyloxyadenine; fitness penalty; ferroptosis; detoxification
• ISSN: 2150-7511; 2150-7511
• DOI: 10.1128/mbio.03177-23

Multi-fungicide resistance (MFR) is a serious environmental problem, which results in the excessive use of fungicides. Fitness penalty, as a common phenomenon in MFR, can partially counteract the issue of resistance due to the weakened vigor of MFR pathogens. Their underlying mechanism and relationship remain unexplained. By Oxford Nanopore Technologies sequencing and dot blot, we found that N6-methyloxyadenine (6mA) modification, the dominate epigenetic marker in , was significantly altered after MFR emerged. Among the differently methylated genes, could efficiently detoxify SYP-14288, a novel uncoupler, through complexing the fungicide with glutathione and induce MFR. Interestingly, overexpression was induced by elevated 6mA levels and chromatin accessibility to its genomic loci. Moreover, the overexpression led to reactive oxygen species burst and ferroptosis in SYP-14288-resistant mutants, which enhanced the resistance and induced fitness penalty in through triggering low energy shock adaptive response. Furthermore, this study revealed that the 6mA-PcGSTZ1-ferroptosis axis could mediate intergenerational resistance memory transmission and enabled adaptive advantage to . In conclusion, the findings provide new insights into the biological role of 6mA as well as the mechanisms underlying the trade-off between MFR and fitness. These could also benefit disease control through the blockade of the epigenetic axis to resensitize resistant isolates.IMPORTANCEN6-methyloxyadenine (6mA) modification on DNA is correlated with tolerance under different stress in prokaryotes. However, the role of 6mA in eukaryotes remains poorly understood. Our current study reveals that DNA adenine methyltransferase 1 (DAMT1)-mediated 6mA modification at the upstream region of GST zeta 1 (GSTZ1) is elevated in the resistant strain. This elevation promotes the detoxification uncoupler and induces multifungicide resistance (MFR). Moreover, the overexpression led to reactive oxygen species burst and ferroptosis in SYP-14288-resistant mutants, which enhanced the resistance and induced fitness penalty in through triggering low energy shock adaptive response. Furthermore, this study revealed that the 6mA-PcGSTZ1-ferroptosis axis could mediate intergenerational resistance memory transmission and enabled adaptive advantage to . Overall, our findings uncover an innovative mechanism underlying 6mA modification in regulating PcGSTZ1 transcription and the ferroptosis pathway in .