Streptococcus suis regulates central carbon fluxes in response to environment to balance drug resistance and virulence.

Streptococcus suis, a zoonotic pathogen, must adapt to the distinct nutritional environment of the host microhabitat during infection and the establishment of invasive disease, primarily by modulating its metabolic pathways. Metabolic plasticity endows S. suis with an enhanced capacity for environmental adaptation. Multidrug-resistant S. suis is increasingly prevalent due to the extensive use of antibiotics in swine production. In this study, an environment-dependent evolutionary model demonstrated that S. suis could modulate its metabolism in response to environmental changes, thereby altering its drug resistance and virulence. The central carbon flux regulated by pyruvate dehydrogenase (PDH) was identified as a pivotal node in balancing drug resistance and virulence in S. suis. Within the in vivo host environment, increased carbon flux through PDH enhances the production of capsular polysaccharide (CPS), thereby improving immune evasion. Conversely, in the antibiotic environment, reduced carbon flux through PDH downregulates the bacterial metabolic state, which diminishes the induction of toxic metabolites by antibiotics, thereby augmenting drug resistance. This concept provides a reasonable explanation for the puzzling phenomena observed with S. suis in clinical settings. For instance, antibiotic-resistant S. suis has a survival advantage in pig farms where antibiotics are frequently used but is less frequently associated with invasive infections. Furthermore, this study demonstrates that exogenous pyruvate can enhance the bactericidal effect of gentamicin against clinically multidrug-resistant S. suis, offering new insights and potential strategies for controlling clinical multidrug-resistant S. suis infections.