Cordycepin suppresses growth and virulence of Magnaporthe oryzae via mitochondrial function and carbonic anhydrase-associated nitrogen metabolism

Cordycepin, a nucleoside analog naturally produced by Cordyceps fungi, exhibits broad-spectrum biological activity and has been reported to inhibit both prokaryotic and eukaryotic microorganisms, although its antifungal mechanisms remain poorly understood. In this study, we systematically evaluated the inhibitory effects of cordycepin on the growth, development, and pathogenicity of Magnaporthe oryzae, the causal agent of rice blast, and further elucidated its mode of action through transcriptomic analysis and gene function validation. Cordycepin significantly inhibited hyphal growth and reduced both conidial production and germination in a dose-dependent manner. Moreover, it severely impaired appressorium formation and increased the frequency of malformed structures, ultimately leading to attenuated virulence. Transcriptome profiling revealed that cordycepin reprogrammed multiple metabolic and signaling pathways, including nitrogen metabolism, fatty acid metabolism, melanin and chitin biosynthesis, and protein kinase networks. Notably, two carbonic anhydrase genes, MoCA1 and MoCA5, were significantly downregulated and identified as candidate genes responsive to cordycepin. Functional analysis showed that MoCA5 localizes to mitochondria and interacts with MoCA1; deletion of either gene resulted in disrupted mitochondrial membrane potential, reduced ATP synthesis, and decreased pathogenicity. Collectively, our results indicate that cordycepin suppresses the growth and virulence of M. oryzae through coordinated modulation of mitochondrial function and nitrogen metabolism – associated pathways. These findings provide new insights into the antifungal action of cordycepin and identify potential molecular components involved in fungal metabolic adaptation to cordycepin stress.