Harnessing Human Milk Oligosaccharides and Ellagic Acid Glycosides to Combat Group B Streptococcus

Abstract

Group B Streptococcus (GBS) is a bacterium ubiquitous in human health that acts as both commensal and pathogen. While adults are often passively colonized with GBS, infants are particularly susceptible to invasive GBS infection and resultantly the transmission of GBS from adults to infants presents a significant risk for preterm birth and other adverse pregnancy outcomes. This heightened burden of GBS infection on neonatal health makes it of prime interest for the continued discovery and development of new antibiotics and therapeutic strategies. Herein we identify and interrogate the antibacterial activity of novel small molecule antibiotics in treating GBS infections. We demonstrate that human milk oligosaccharides (HMOs) can be used as antibiotic adjuvants to reverse antifolate resistance in GBS. We conduct untargeted metabolomics to reveal that HMOs perturb lipid recruitment and biosynthesis in GBS and we also synthesize a set of bioorthogonal HMO tools to enable further target identification studies. Additionally, we investigate the synthesis and ability of ellagic acid glycosides to inhibit GBS biofilm formation and early adhesion mechanisms. Taken together, these antibiotic strategies will enable the development of selective therapeutics to prevent GBS transmission and limit deleterious effects to the infant microbiome.