Synthesis and immunological evaluation of the lipopolysaccharide outer core of Salmonella for potential broad-spectrum protection against multiple Salmonella serovars

Salmonella species (Salmonella spp.) are a major foodborne pathogen and a leading cause of gastroenteritis in humans. The emergence and continued spread of multidrug-resistant Salmonella spp. suggest the urgent need for novel vaccines to complement antibiotics. Currently, there are no approved vaccines against Salmonella spp. for human use beyond those for Salmonella enterica (S. enterica) serovar Typhi. To address this gap, oligosaccharides corresponding to the lipopolysaccharide (LPS) outer core of S. enterica were investigated as potential antigens that can target multiple pathogenic Salmonella serovars. An efficient chemical synthesis strategy was developed to stereoselectively construct the sterically congested outer core pentasaccharides with five 1,2-cis glycosidic linkages. These synthetic glycan antigens were conjugated to the mutant bacteriophage Qβ, a highly immunogenic carrier system. The resulting constructs elicited strong and durable anti-glycan IgG antibodies, which can robustly bind to Salmonella spp. with truncated LPS (rough strain). For smooth strains bearing long LPS chains, the combination of the antisera with the antimicrobial peptide thanatin, an inhibitor of the LPS transport system, exhibited enhanced cytotoxicity toward multiple serovars of pathogenic Salmonella, suggesting that combination therapy may serve as a strategy for enhancing protection against salmonellosis.