Zhao Jinxin, Zhu Yan, Han Jiru, Lin Yu-Wei, Aichem Michael, Wang Jiping, Chen Ke, Velkov Tony, Schreiber Falk, Li Jian
Infection and Immunity Program, Department of Microbiology, Biomedicine Discovery Institute, Monash University, Clayton, VIC 3800, Australia.
Population Health and Immunity Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia.
Microorganisms. 2020 Nov 16;8(11):1793. doi: 10.3390/microorganisms8111793.
Multidrug-resistant (MDR) is a critical threat to human health globally. We constructed a genome-scale metabolic model AB5075 for the hypervirulent, MDR strain AB5075. Predictions of nutrient utilization and gene essentiality were validated using Biolog assay and a transposon mutant library. In vivo transcriptomics data were integrated with AB5075 to elucidate bacterial metabolic responses to the host environment. AB5075 contains 1530 metabolites, 2229 reactions, and 1015 genes, and demonstrated high accuracies in predicting nutrient utilization and gene essentiality. At 4 h post-infection, a total of 146 metabolic fluxes were increased and 52 were decreased compared to 2 h post-infection; these included enhanced fluxes through peptidoglycan and lipopolysaccharide biosynthesis, tricarboxylic cycle, gluconeogenesis, nucleotide and fatty acid biosynthesis, and altered fluxes in amino acid metabolism. These flux changes indicate that the induced central metabolism, energy production, and cell membrane biogenesis played key roles in establishing and enhancing bloodstream infection. This study is the first to employ genome-scale metabolic modeling to investigate infection in vivo. Our findings provide important mechanistic insights into the adaption of to the host environment and thus will contribute to the development of new therapeutic agents against this problematic pathogen.
多重耐药（MDR）是全球人类健康面临的重大威胁。我们构建了针对高毒力多重耐药菌株AB5075的基因组规模代谢模型AB5075。利用Biolog分析和转座子突变体文库对营养物质利用和基因必需性的预测进行了验证。将体内转录组学数据与AB5075整合，以阐明细菌对宿主环境的代谢反应。AB5075包含1530种代谢物、2229个反应和1015个基因，并在预测营养物质利用和基因必需性方面表现出高精度。与感染后2小时相比，感染后4小时共有146种代谢通量增加，52种代谢通量减少；这些通量变化包括通过肽聚糖和脂多糖生物合成、三羧酸循环、糖异生、核苷酸和脂肪酸生物合成的通量增强，以及氨基酸代谢中的通量改变。这些通量变化表明，诱导的中心代谢、能量产生和细胞膜生物合成在建立和增强血流感染中起关键作用。本研究首次采用基因组规模代谢建模来研究体内感染。我们的发现为该菌适应宿主环境提供了重要的机制性见解，因此将有助于开发针对这种有问题病原体的新型治疗药物。
