Metabolic Model of Streptococcus suis reveals the Indispensability of catabolic ornithine carbamoyltransferase ArcB for Adapting to Anaerobiosis

Pathogenic microorganisms have evolved various strategies to sense and respond to stress in order to establish infection and ensure survival within the host's complex environment. Hypoxia, a metabolic stress factor encountered by aerobic microorganisms during rapid growth, remains poorly understood in terms of pathogen adaptation. Streptococcus suis, a zoonotic pathogen causing meningitis and sepsis, exhibits remarkable adaptability to anaerobic conditions. Transcriptomic analysis reveals that anaerobic conditions significantly suppress carbohydrate metabolism in S. suis SC19 while differentially regulating genes related to toxins, metal uptake systems, and adhesion. A reconstructed genome-scale metabolic network (GSMM), constrained by transcriptomic information, was used to explore metabolic changes in SC19 under hypoxia. Anaerobic metabolism of SC19 is characterized by activation of the arginine deiminase (ADI) pathway and biosynthesis of branched-chain amino acids (BCAA). Enzymes ArcB and IlvH from these pathways were identified as potential targets and docked with drugs from the DrugBank database. Among the candidate inhibitors targeting ArcB, simvastatin and cis-(Z)-flupentixol demonstrated significant hypoxia-dependent inhibition of SC19 survival. Simvastatin was also found to attenuate virulence of SC19, proliferation, and pro-inflammatory capabilities in mice by inhibiting ArcB during the late stage of infection. This study unveils how Streptococcus suis adapts to low oxygen limitations by rewiring amino acid metabolism. A targeted antimicrobial strategy based on metabolic adaptability of pathogen is proposed to alleviate the pressure of developing new drugs against multidrug-resistant bacterial infections. Overall design: To characterizing the impact of hypoxia on streptococcus suis SC19 growth, RNA-seq was utilized to monitor the global transcriptional regulation of SC19 at the mid-log phase (6 h) under oxygen limitation. A comparative analysis of gene expression between aerobic and anaerobic-cultivated SC19 cells revealed a global regulation of the transcriptome in response to hypoxia.