The glycans (oligosaccharides and glycoconjugates) of human milk are powerful pathogen anti-adhesion compounds, and represent a novel class of antimicrobial agents. We propose to synthesize and test two of the most promising prototypes of fucosyl glycans (oligosaccharides and mucin) that naturally occur in human milk and have been shown, from in vitro, in vivo and molecular epidemiologic studies, to strongly inhibit NIAID Category B pathogens Campylobacter, Vibrio cholera, diarrheagenic Escherichia coli, and caliciviruses (noroviruses). These glycans function as receptor analogs that prevent infection by inhibiting pathogen binding to host cell surface glycans. Further, repeated pathogen exposure to such glycans does not result in resistance. Such glycans are stable for prolonged periods at room temperature, are intrinsically pleasant tasting, and could be produced and distributed economically as part of a drink or nutriment to individuals or populations at risk. A major roadblock to preclinical studies and human trials, however, has been the complexity and cost of synthesis of these fucosyl glycans. We propose to use recent breakthroughs in bioengineering for two generations of large-scale synthesis of fucosyl glycans in genetically modified microorganisms. Fucosyl oligosaccharides expressed in a bacterial construct will serve as standard synthetic monovalent inhibitors. A simultaneous but longer second generation of synthesis will be construction of a yeast that produces high molecular weight mucins whose polyvalent and multivalent expression of fucosylated moieties are expected to provide stronger and more broadly effective pathogen inhibition. The synthesis of these fucosyl glycans and their preclinical testing would be a quantum step towards a novel family of broadly effective therapeutics and prophylactics, would bring us to the threshold of human trials against Category B pathogens, and would represent a powerful new instrument for biodefense.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01AI075563-05
Application #
7934513
Study Section
Special Emphasis Panel (ZAI1-MH-M (M2))
Program Officer
Hall, Robert H
Project Start
2007-09-01
Project End
2014-08-31
Budget Start
2011-09-01
Budget End
2014-08-31
Support Year
5
Fiscal Year
2011
Total Cost
$890,257
Indirect Cost
Name
Boston College
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
045896339
City
Chestnut Hill
State
MA
Country
United States
Zip Code
02467
Newburg, David S; Ko, Jae Sung; Leone, Serena et al. (2016) Human Milk Oligosaccharides and Synthetic Galactosyloligosaccharides Contain 3'-, 4-, and 6'-Galactosyllactose and Attenuate Inflammation in Human T84, NCM-460, and H4 Cells and Intestinal Tissue Ex Vivo. J Nutr 146:358-67
He, YingYing; Lawlor, Nathan T; Newburg, David S (2016) Human Milk Components Modulate Toll-Like Receptor-Mediated Inflammation. Adv Nutr 7:102-11
Newburg, David S; He, Yingying (2015) Neonatal Gut Microbiota and Human Milk Glycans Cooperate to Attenuate Infection and Inflammation. Clin Obstet Gynecol 58:814-26
Newburg, David S; Morelli, Lorenzo (2015) Human milk and infant intestinal mucosal glycans guide succession of the neonatal intestinal microbiota. Pediatr Res 77:115-20
Hill, David R; Newburg, David S (2015) Clinical applications of bioactive milk components. Nutr Rev 73:463-76
Newburg, David S; Grave, Gilman (2014) Recent advances in human milk glycobiology. Pediatr Res 75:675-9
He, Y; Liu, S; Leone, S et al. (2014) Human colostrum oligosaccharides modulate major immunologic pathways of immature human intestine. Mucosal Immunol 7:1326-39
Newburg, D S (2013) Glycobiology of human milk. Biochemistry (Mosc) 78:771-85
Kling, David E; Tsvang, Inna; Murphy, Miriam P et al. (2013) Group B Streptococcus induces a caspase-dependent apoptosis in fetal rat lung interstitium. Microb Pathog 61-62:1-10
Wiederschain, G Ya (2013) Glycobiology: progress, problems, and perspectives. Biochemistry (Mosc) 78:679-96

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