Infectious diseases remain the leading cause of death worldwide. With bacterial resistance on the rise, a deeper understanding of the fundamental biology of bacteria is essential. Protein glycosylation systems have recently been identified in virtually all bacterial pathogens, yet remain a largely unexplored frontier in microbial science. In this project, we are developing enzyme inhibitors for a key step in bacterial protein N-glycosylation. The new inhibitors will be powerful tools to study the interplay of protein glycosylation and virulence in respiratory pathogens such as Haemophilus influenzae, and a potential starting point for the development of a new class of “glycobiotics”.
Tytgat, H. L. P. & Lebeer, S. “The Sweet Tooth of Bacteria: Common Themes in Bacterial Glycoconjugates.” Microbiol. Mol. Biol. Rev. 78, 372-417 (2014)
Schwarz, F., Fan, Y.-Y., Schubert, M. & Aebi, M. “Cytoplasmic N-Glycosyltransferase of Actinobacillus pleuropneumoniae Is an Inverting Enzyme and Recognizes the NX(S/T) Consensus Sequence.” J. Biol. Chem. 286, 35267-35274 (2011)
Grass, S., Buscher, A.Z., Swords, W.E., Apicella, M.A., Barenkamp, S.J., Ozchlewski, N. & St Geme III, J.W. “The Haemophilus influenzae HMW1 adhesin is glycosylated in a process that requires HMW1C and phosphoglucomutase, an enzyme involved in lipooligosaccharide biosynthesis.” Mol. Microbiol. 48, 737-751 (2003)
Scott, D.E., Coyne, A.G., Hudson, S.A. & Abell, C. “Fragment-Based Approaches in Drug Discovery and Chemical Biology” Biochemistry 51, 4990-5003 (2012).
Allen, R.C., Popat, R., Diggle, S.P. & Brown, S.P. “Targeting virulence: can we make evolution-proof drugs?” Nat. Rev. Microbiol. 12, 300-308 (2014).