DataSheet_2_Genome-scale metabolic modeling and in silico analysis of opportunistic skin pathogen Cutibacterium acnes.zip

Cutibacterium acnes, one of the most abundant skin microbes found in the sebaceous gland, is known to contribute to the development of acne vulgaris when its strains become imbalanced. The current limitations of acne treatment using antibiotics have caused an urgent need to develop a systematic strategy for selectively targeting C. acnes, which can be achieved by characterizing their cellular behaviors under various skin environments. To this end, we developed a genome-scale metabolic model (GEM) of virulent C. acnes, iCA843, based on the genome information of a relevant strain from ribotype 5 to comprehensively understand the pathogenic traits of C. acnes in the skin environment. We validated the model qualitatively by demonstrating its accuracy prediction of propionate and acetate production patterns, which were consistent with experimental observations. Additionally, we identified unique biosynthetic pathways for short-chain fatty acids in C. acnes compared to other GEMs of acne-inducing skin pathogens. By conducting constraint-based flux analysis under endogenous carbon sources in human skin, we discovered that the Wood-Werkman cycle is highly activated under acnes-associated skin condition for the regeneration of NAD, resulting in enhanced propionate production. Finally, we proposed potential anti-C. acnes targets by using the model-guided systematic framework based on gene essentiality analysis and protein sequence similarity search with abundant skin microbiome taxa.

痤疮丙酸杆菌（Cutibacterium acnes）是皮脂腺中最为丰富的皮肤微生物之一，当其菌株失衡时，被证实会推动寻常痤疮（acne vulgaris）的发生发展。当前抗生素治疗痤疮的局限性日益凸显，亟需开发可选择性靶向痤疮丙酸杆菌的系统性策略，而该目标可通过解析该菌在多种皮肤环境下的细胞行为得以实现。为此，本研究基于5型核糖体分型（ribotype 5）相关菌株的基因组信息，构建了致病性痤疮丙酸杆菌的基因组规模代谢模型（genome-scale metabolic model, GEM）iCA843，以期全面解析该菌在皮肤环境中的致病特性。我们通过验证模型对丙酸与乙酸生成模式的预测准确性（该结果与实验观测结果一致），完成了模型的定性验证。此外，相较于其他致痤疮皮肤病原体的基因组规模代谢模型，我们发现痤疮丙酸杆菌存在独特的短链脂肪酸生物合成通路。通过在人体皮肤内源性碳源条件下开展基于约束的通量分析，本研究发现伍德-沃克曼循环（Wood-Werkman cycle）在痤疮相关皮肤环境中被高度激活，以实现烟酰胺腺嘌呤二核苷酸（NAD）的再生，进而增强丙酸的生成。最后，我们依托基于基因必需性分析、结合针对丰富皮肤微生物类群的蛋白质序列相似性搜索所构建的模型引导系统性分析框架，提出了潜在的抗痤疮丙酸杆菌靶点。