Community-acquired pneumonia remains a major contributor towards global communicable disease-mediated morbidity and mortality despite the availability of protective vaccines and effective antibiotics. The glycocalyx is a dense layer rich in glycoproteins, glycosaminoglycans and proteoglycans, which also harbors a variety of sugars including fucose. Despite their abundance in the lungs, the contribution of fucosylated glycans towards bacterial pathogenesis remains largely unexplored. In this study we aim to understand the role of ?-(1,2)-fucose, which is a common capping structure of various antigens, in the context of host-pathogen interactions and pulmonary inflammation. For this, we utilized 2-deoxy-D-galactose (2-DG), an inhibitor of ?-(1,2)-fucosylation, in murine and human models of pneumococcal pneumonia. Treatment with 2-DG effectively inhibited ?-(1,2)-fucosylation in a 3D model of human bronchial epithelial cells. In mice intranasally infected with Streptococcus pneumoniae (Spn), 2-DG treatment markedly improved physiological parameters such as infection-induced body weight and temperature loss. Treatment with 2-DG also resulted in reduced bacterial burden in bronchoalveolar lavage (BAL) fluid and lung tissue following Spn infection. Flow cytometry revealed reduced neutrophil infiltration into BAL of Spn-infected mice upon 2-DG treatment, compared to sham-treated infected mice. Furthermore, 2-DG treatment markedly improved lung barrier function and led to decreased IL-6 and TNF-? production in Spn-infected mice. Taken together, we conclude that 2-DG treatment prevents the establishment of pneumococcal infection in mice.