Glutathione Synthesis Contributes to Virulence of in a Murine Model of Sepsis.

, a leading cause of sepsis and meningitis in neonates, utilizes multiple virulence factors to survive and thrive within the human host during an infection. Unique among the pathogenic streptococci, uses a bifunctional enzyme encoded by a single gene () to synthesize glutathione (GSH), a major antioxidant in most aerobic organisms. Since can also import GSH, similar to all other pathogenic streptococcal species, the contribution of GSH synthesis to the pathogenesis of disease is not known. In the present study, deletion mutants were generated in strains representing three of the most prevalent clinical serotypes of and were compared against isogenic wild-type and knock-in strains. When cultured in a chemically defined medium under nonstress conditions, each mutant and its corresponding wild type had comparable growth rates, generation times, and growth yields. However, deletion mutants were found to be more sensitive than wild-type or knock-in strains to killing and growth inhibition by several different reactive oxygen species. Furthermore, deletion of in strain COH1 significantly attenuated virulence compared to the wild-type or knock-in strains in a mouse model of sepsis. Taken together, these data establish that GSH is a virulence factor important for resistance to oxidative stress and that GSH synthesis plays a crucial role in pathogenesis and further suggest that the inhibition of GSH synthesis may provide an opportunity for the development of novel therapies targeting disease. Approximately 10 to 30% of women are naturally and asymptomatically colonized by However, transmission of from mother to newborn during vaginal birth is a leading cause of neonatal meningitis. Although colonized mothers who are at risk for transmission to the newborn are treated with antibiotics prior to delivery, is becoming increasingly resistant to current antibiotic therapies, and new treatments are needed. This research reveals a critical stress resistance pathway, glutathione synthesis, that is utilized by and contributes to its pathogenesis. Understanding the role of this unique bifunctional glutathione synthesis enzyme in during sepsis may help elucidate why produces such an abundance of glutathione compared to other bacteria.