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Background
Streptococcus pneumoniae is a Gram-positive enveloped bacterium that is the main pathogen causing invasive pneumococcal diseases such as pneumonia, sepsis, meningitis, and otitis media. For young children, the elderly and immunocompromised patients infection with pneumococcus can lead to serious illness. Most pneumococcal strains have a polysaccharide capsule, and Streptococcus pneumoniae can be categorized into serotypes based on their expression of different structures of capsular polysaccharides (CPS), of which about 20 are highly virulent and cause 90% of pneumococcal disease. The severity of pneumococcal infection depends on the serotype of Streptococcus pneumoniae.
Pneumococcal vaccines currently approved for use are made using bacterial CPS of the actual pneumococcal serotype or CPS ligated to a protein carrier with the addition of an adjuvant. Streptococcus pneumoniae serotype 8 is part of the first-generation polysaccharide vaccine, PPV23, whose CPS consists of linear tetrasaccharide repeating units that share a common cellulosic aldose disaccharide sequence with the pneumococcal serotype 3 CPS. Strains of this serotype are resistant to antibiotics such as erythromycin, lincomycin, tetracycline and ciprofloxacin. In addition, this multi-drug resistant serotype is most often found in HIV-infected individuals.
To determine the structure of the protective epitope, the investigators synthesized a series of all possible monosaccharide sequences (58a-61a) including the tetrasaccharide repeating unit CP by moving the reading frame, which showed that the tetrasaccharide (60a) binds best to a protective monoclonal antibody against serotype 8 native CP. Further localization of the protective epitope in tetrasaccharide (60a) revealed that the presence of glucuronic acid residues did not play an important role. The study also demonstrated the possibility of using couplers of synthetic oligosaccharide ligands in conjunction with coupled polysaccharide vaccines. Some serotypes have structural features that result in their CP not being sufficiently active in vaccines, and this approach may be useful for these problematic serotypes.
Figure 1. Structure of the capsular polysaccharide of S. pneumoniae serotype 8 (repeating unit (57)), synthetic oligosaccharide derivatives (59a–62a), and conjugates with CRM197 (series b) (Source: Gening ML, et al. 2021)
1. Gening ML, et al. Synthetic Analogs of Streptococcus pneumoniae Capsular Polysaccharides and Immunogenic Activities of Glycoconjugates. Russ J Bioorg Chem. 2021;47(1):1-25.
2. Javed, et al. Bacterial surface capsular polysaccharides from Streptococcus pneumoniae: A systematic review on structures, syntheses, and glycoconjugate vaccines. Carbohydr Res. 2021 Apr;502:108277.
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References
Effects of Capsular Polysaccharide amount on Pneumococcal-Host interactions
Among the many oral streptococci, Streptococcus pneumoniae (Spn) stands out for the capacity of encapsulated strains to cause invasive infection. Spread beyond upper airways, however, is a biological dead end for the organism, raising the question of the benefits of expending energy to coat its surface in a thick layer of capsular polysaccharide (CPS). In this study, we compare mutants of two serotypes expressing different amounts of CPS and test these in murine models of colonization, invasion infection and transmission. Our analysis of the effect of CPS amount shows that Spn expresses a capsule of sufficient thickness to shield its surface from the deposition of complement and binding of antibody to underlying epitopes. While effective shielding is permissive for invasive infection, its primary contribution to the organism appears to be in the dynamics of colonization. A thicker capsule increases bacterial retention in the nasopharynx, the first event in colonization, and also impedes IL-17-dependent clearance during late colonization. Enhanced colonization is associated with increased opportunity for host-to-host transmission. Additionally, we document substantial differences in CPS amount among clinical isolates of three common serotypes. Together, our findings show that CPS amount is highly variable among Spn and could be an independent determinant affecting host interactions.
Exploring Zingiber officinale bioactive compounds for inhibitory effects on Streptococcus pneumoniae capsular polysaccharide biosynthesis proteins: In silico study
Pak J Pharm Sci
Authors: Azmi MB, Noori MY, Haseen Ahmed SD, Alotaibi BS, Naeem S, Kazi M, Islam M, Wadood A.
The capsule is a major virulence factor for Streptococcus pneumoniae which causes global morbidity and mortality. It is already known that there are few conserved genes in the capsular biosynthesis pathway, which are common among all known serotypes, called CpsA, CpsB, CpsC and CpsD. Inhibiting capsular synthesis can render S. pneumoniae defenseless and vulnerable to phagocytosis. The Inhibitory potential of active Zingiber officinale compounds was investigated against the 3D (3-dimensional) structural products of Cps genes using in silico techniques. A 3D compound repository was created and screened for drug-likeness and the qualified compounds were used for molecular docking and dynamic simulation-based experiments using gallic acid for outcome comparison. Cavity-based docking revealed five different cavities in the CpsA, CpsB and CpsD proteins, with gallic acid and selected compounds of Zingiber in a binding affinity range of -6.8 to -8.8 kcal/mol. Gingerenone A, gingerenone B, isogingerenone B and gingerenone C showed the highest binding affinities for CpsA, CpsB and CpsD, respectively. Through the Molegro Virtual Docker re-docking strategy, the highest binding energies (-126.5 kcal/mol) were computed for CpsB with gingerenone A and CpsD with gingerenone B. These findings suggest that gingerenone A, B and C are potential inhibitors of S. pneumoniae-conserved capsule-synthesizing proteins.