Human milk oligosaccharides (HMOs) are glycans that are unique in structure and composition to human breast milk. Although these compounds are known to provide infants with a wide variety of health benefits including protection against pathogens, much remains unknown about the activities of single-entity HMOs. This results from an inability to isolate homogenous HMOs from breast milk in large milligram quantities coupled with the difficulties of carbohydrate synthesis. To address this limitation, we recently initiated a research program aimed at developing scalable chemical syntheses of several common HMOs. Our laboratory recently conducted HMO mass fingerprinting studies that revealed the structures of tetraose and mono- and difucosylated tetraose HMO structures in several donor breast milk samples. In accordance with these findings, we first completed a scalable synthesis of the ubiquitous HMO lacto-N-tetraose (LNT). We are currently modifying this route to LNT to synthesize the following mono- and difucosylated LNT derivatives: lacto-N-fucopentaose I, lacto-N-fucopentaose II, and lacto-N-difucohexaose I. In addition to developing scalable chemical syntheses of HMOs, our research program is aimed at determining the effects of HMOs on Group B Streptococcus (GBS) and investigating the nature of carbohydrate localization in GBS. GBS is a gram-positive bacterial pathogen that is a leading cause of neonatal morbidity and mortality worldwide. To conduct the localization studies, we will first incorporate an azide functionality into the synthetic HMOs. We can then selectively label these compounds in vivo using a copper-free, strain-promoted [3+2] cycloaddition, or click reaction, with strained cyclooctyne fluorophore conjugates. Confocal fluorescent imaging of the cellular environment will then allow us to determine where the HMOs are localized by GBS.

Synthesis of human milk oligosaccharides and determination of their localization in Group B Streptococcus

254th National Meeting (2017)

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