Bacterial pathogens can exploit metabolic pathways to facilitate their successful infection cycles, but little is known about roles of d-galactosamine (GalN)/N-acetyl-d-galactosamine (GalNAc) catabolism pathway in bacterial pathogenesis. Here, we report the genomic reconstruction of GalN/GalNAc utilization pathway in Streptococci and the diversified aga regulons. We delineated two new paralogous AgaR regulators for the GalN/GalNAc catabolism pathway. The electrophoretic mobility shift assays experiment demonstrated that AgaR2 (AgaR1) binds the predicted palindromes, and the combined in vivo data from reverse transcription quantitative polymerase chain reaction and RNA-seq suggested that AgaR2 (not AgaR1) can effectively repress the transcription of the target genes. Removal of agaR2 (not agaR1) from Streptococcus suis 05ZYH33 augments significantly the abilities of both adherence to Hep-2 cells and anti-phagocytosis against RAW264.7 macrophage. As anticipated, the dysfunction in AgaR2-mediated regulation of S. suis impairs its pathogenicity in experimental models of both mice and piglets. Our finding discovered two novel regulators specific for GalN/GalNAc catabolism and assigned them distinct roles into bacterial infections. To the best of our knowledge, it might represent a first paradigm that links the GalN/GalNAc catabolism pathway to bacterial pathogenesis. Bacterial pathogens including Streptococcus species have evolved multiple strategies to hijack/exploit metabolic pathways for facilitating their successful infection cycles. Although that the two amino sugars (d-galactosamine [GalN] and N-acetyl-d-galactosamine [GalNAc]) function as the common components of various cell surface structures and are required for three domains of life, this metabolism is poorly known in Streptococcus species. Nothing is elucidated regarding the relevance of GalN/GalNAc catabolism pathway to bacterial pathogenesis. We report, for the first time, the genomic reconstruction of GalN/GalNAc utilization pathway with variations in Firmicutes (and/or Streptococci) and the diversified aga regulons. More importantly, we are first to define that the maintenance/regulation of GalN/GalNAc utilization pathway contributes to Streptococcal infections. To the best of our knowledge, it represents a first paradigm that links the GalN/GalNAc catabolism pathway to bacterial pathogenesis. © 2015 Published by John Wiley & Sons Ltd.