Penicillium digitatum is the most destructive postharvest pathogen of citrus fruits, causing substantial economic losses. Prochloraz-resistant strains have emerged due to overuse of imidazole fungicides in agriculture. To study the prochloraz resistance mechanisms at the system level, a genome-scale metabolic model (GEM, iPD1512) of P. digitatum was reconstructed and constrained based on context-specific transcriptome data of the prochloraz-resistant strain, PdF6, from our previous work, a newly sequenced, context-specific transcriptome result of the major facilitator superfamily transporter-encoding gene mfs2 knockout mutant PdF6Δmfs2, and experimentally derived growth rate data. Through the model, iPD1512, the processes of prochloraz resistance in P. digitatum were well simulated. In detail, the growth rates of both wild-type and mutant P. digitatum under different prochloraz concentrations were simulated using constraint-based reconstruction and analysis. The growth rates of the mutant strains (sterol regulatory element-binding protein-encoding gene sreA knockout mutant PdF6ΔsreA and PdF6Δmfs2) were calculated and confirmed to be consistent with the simulation results. Furthermore, correlations between genes and prochloraz resistance were predicted and showed a great difference when compared with correlation results based on p-values from the hypothesis testing used by comparative transcriptomics. To sum up, in contrast to traditional transcriptome analysis, the GEM provides a systemic and dynamic drug resistance mechanism, which might help to detect some key upstream regulatory genes, but with small expression changes, and might provide more efficient targets to control prochloraz-resistant P. digitatum.

中文翻译：

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基于基因组规模代谢模拟的上下文特定模型的重建，用于鉴定指状青霉中的丙氯灵抗性机制

指状青霉是柑橘类水果采后危害最大的病原菌，造成了巨大的经济损失。由于在农业中过度使用咪唑类杀菌剂，已经出现了耐丙氯灵的菌株。研究丙氯灵抗性机制在系统级，一个基因组范围的代谢模型（GEM，iPD1512）状青霉被重建和约束基于从我们以前的工作耐丙氯灵-应变，PdF6，的上下文特定的转录组数据，主要促进子超家族转运蛋白编码基因mfs2敲除突变体 PdF6Δ mfs2的新测序、上下文特异性转录组结果，以及实验得出的增长率数据。通过模型，iPD1512，咪鲜胺中电阻的处理状青霉被很好地模拟。详细地，使用基于约束的重建和分析模拟了不同原氯灵浓度下野生型和突变体P. digitatum的生长速率。计算突变菌株（甾醇调节元件结合蛋白编码基因sreA敲除突变体 PdF6Δ sreA和 PdF6Δ mfs2）的生长速率并确认与模拟结果一致。此外，预测了基因与丙氯灵抗性之间的相关性，并与基于相关性结果的相关性结果显示出很大差异来自比较转录组学使用的假设检验的p 值。综上所述，与传统的转录组分析相比，GEM 提供了一种系统的、动态的耐药机制，这可能有助于检测一些关键的上游调控基因，但表达变化很小，并可能提供更有效的靶点来控制丙氯胺耐药P. digitatum。