Novel translational strategies to combat group B streptococcus infections

Group B streptococcus (GBS) is a major human pathogen that infects diverse anatomic sites and cause wide spectrum of disease manifestations. GBS infections are the leading cause of stillbirths, preterm births and neonatal mortality worldwide. The existing control measures to treat or prevent human GBS infections are significantly challenged by the lack of a human vaccine as well as the rise in antibiotic resistance among GBS strains. Thus, novel translational approaches are urgently required to treat GBS infections. We discovered that a human probiotic produces a previously unknown antibiotic, salivabactin, that is potent in inhibiting the growth of pathogenic streptococci in vitro and in vivo. We also found that the probiotic bacteria produce salivabactin only transiently, which contributes to its reduced probiotic efficacy. To overcome this, we engineered the probiotic to augment salivabactin production and showed its improved prophylactic efficacy in vivo. However, the potency of salivabactin and engineered probiotic in preventing or treating GBS infections remain unknown. The primary objective of this proposal to evaluate the translational potential of two novel strategies, salivabactin and engineered probiotic, to treat or prevent GBS infections in preclinical mouse models of infection simulating various human disease manifestations. We will test our central hypothesis that salivabactin and salivabactin- hyperproducing engineered probiotic are efficacious in controlling GBS infections in two specific aims. The completion of this study will fully assess the translational potential of two novel therapeutic and prophylactic strategies to treat streptococcal infections and identify new antibiotic- and probiotic-based strategies to combat GBS infections.