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Heterogenous expression of Sclerotinia sclerotiorum β-tubulin conferring benzimidazole-resistance in Fusarium asiaticum

Ying Yang: Nanjing Agricultural University

<div>In many filamentous fungi, only one β-tubulin exists in the genome and its specific point mutations confer resistance to benzimidazole fungicides. <em>Fusarium asiaticum </em>has two β-tubulins, β<sub>1</sub>- and β<sub>2</sub>-tubulin. Homology of β<sub>1</sub>-tubulin is higher than β<sub>2</sub>-tubulin with β-tubulin of other filamentous fungi. Interestingly, the resistance of <em>F. aisaticum</em> to benzimidazoles is primarily due to the point mutations of β<sub>2</sub>-tubulin. Recently, many studies that the point mutation of β-tubulin regulates resistance to benzimidazoles were widely reported in filamentous fungi. Molecular docking between drugs and target β-tubulin was analyzed by computer software. However, molecular mechanism of resistance has not been elucidated. In our previous study, the E198A genotype of <em>Botrytis cinerea</em> conferring benzimidazole-resistance replaced the β<sub>2</sub>-tubulin locus in <em>F. asiaticum</em>. This heterogenous expression can’t exhibit benzimidazole resistance. One possible cause is that the E198A genotype was not reported in <em>F. asiaticum</em>. To further confirm whether heterogenous expression of the same mutated genotype existing in both <em>F. asiaticum</em> and <em>Sclerotinia sclerotiorum</em> can regulate drug-resistance, the β<sub>1</sub>-tubulin and β<sub>2</sub>-tubulin locus of <em>F. asiaticum</em> was replaced with the F200Y genotype of <em>S. sclerotiorum</em>, respectively. Both the mutants were still sensitive to benzimidazoles. Furtherly, both β<sub>1</sub>-tubulin and β<sub>2</sub>-tubulin locus of <em>F. asiaticum</em> were replaced with the F200Y genotype of <em>S. sclerotiorum</em>. Surprisingly, the mutants were resistant to benzimidazole. These results indicate that genetic and resistance evolution of β-tubulin in filamentous fungi is more complex than we thought and provide critical insights not only into possible drug-resistance mechanism but also on the design of novel tubulin inhibitors with improved properties.</div>