Development of synthetic fragments of the capsular polysaccharide derived from Acinetobacter baumannii LAC-4 strain

Acinetobacter baumannii (Ab) is a highly adaptable opportunistic pathogen, well-known for its multidrug resistance and growing incidence in both hospital-acquired and community-acquired infections, that can lead to severe diseases such as pneumonia or critical urinary tract states. Its ability to persist on surfaces for extended durations enhances its survival in healthcare settings, posing a major global health challenge. Consequently, studying its virulence mechanisms is essential for the development of new therapeutic strategies and vaccines. Among various strains, the LAC-4 strain has been identified as hypervirulent in a murine intranasal infection model, displaying significantly higher pathogenicity compared to other clinical and laboratory isolates of A. baumannii. Notably, LAC-4 demonstrates robust serum resistance and effectively mimics key aspects of human pulmonary infection, including systemic spreading and bacteremia. The capsular polysaccharide of LAC-4 consists of trisaccharide repeating units (1, Figure 1), comprising N-acetyl-α-D-glucosamine (a), N-acetyl-α-L-fucosamine (b), and α-8-epi-legionaminic acid (c). Synthetic fragments of this polysaccharide are valuable tools for probing interactions with immune system receptors and for antigen mapping, with the ultimate goal of developing semisynthetic glycoconjugate vaccines that may offer protection against Ab infections. In light of this, our group initiated the synthesis of LAC-4 polysaccharide fragments, including both the core trisaccharide repeating unit and extended oligomers. In this communication, we describe our achievements in the design and synthesis of the LAC-4 trisaccharide repeating unit, including the synthesis of the rare 8-epi-legionaminic acid residue. The resulting synthetic glycans will be chemically conjugated to various carriers, such as immunogenic proteins and nanoparticles, for subsequent immunological evaluation.