Research progress on the chemical synthesis of carbohydrate antigens from three highly drug-resistant bacteria
Drug-resistant bacterial infections are significant global threats,resulting in millions of deaths annually and posing serious risks to human health.The emergence of antimicrobial resistance has the potential to result in consequences that are more severe than those seen with COVID-19 in the future.The growing resistance of bacteria weakens the effectiveness of antibiotics,making vaccination a crucial strategy to prevent infection caused by drug-resistant bacteria.Surface-exposed carbohydrates on pathogens are often immunogenic and are considered as potential candidates for carbohydrate-based vaccine development.Commercial glycoconjugate vaccines are currently being utilized for the prevention of diseases such as bacteremia,pneumonia,and meningitis caused by Streptococcus pneumoniae,Haemophilus influenzae type b,and Neisseria meningitidis,resulting in the saving of millions of lives every year.Most of licenced glycoconjugate vaccines are constructed using polysaccharides isolated from bacterial surface in historically.Naturally isolated polysaccharides pose challenges due to their non-uniform components and mixed potential microbial contaminants,which limited the quality improvement of the glycoconjugate vaccines.Additionally,not all pathogens can be feasible to culture on a large scale.Chemical synthetic carbohydrate antigens with well-defined and high pure structures offer a desirable tool for identifying the best epitope and designing the next generation of glycoconjugate vaccines.This review highlights recent advancements in the chemical synthesis of complex carbohydrate antigens derived from the surfaces of three high drug-resistant bacteria.All three bacteria have been listed as antibiotic-resistant"priority pathogens"by World Health Organization in 2017,and currently,there are no vaccines against these bacterial infections.The discussion includes the synthesis of conserved core oligosaccharides and O antigens from H.pylori LPS,as well as the synthesis of Psl exopolysaccharide fragments,A-band trisaccharide repeating unit,Pilin glycan trisaccharide,and O antigens derived from the surface of different P.aeruginosa strains.Additionally,reports have been made on seven subunits of varied O antigens and seven fragments of diverse CPSs from different A.baumannii strains.The high steric hindrance has been overcome by finely tuned assembly sequences.The match and mismatch between the glycosyl donor and acceptor were addressed by a judicious choice of electron-withdrawing or electron-donating protecting group.The construction of the 1,2-cis-glycosidic bonds were accomplished through the utilization of the remote participation effect,the steric hindrance effect or the ring conformation locking effect of the protecting group.The reaction conditions,such as reaction temperature,time,concentration,additives and solvents have significant impacts on the efficiency and selectivity of the glycosylation.De novo synthesis strategy,one-pot glycosylation strategy and pre-activation strategy have been applied for the synthesis of oligosaccharides/polysaccharides from surface of various pathogens.Tremendous progresses have been made for the assembly of complex glycans and glycoconjugate in recent times.Glycan homopolymers as large as 151-mers has been achieved by automated solid phase synthesis in 2020.An arabinans up to a 1080-mer have been synthesized using the automated solution phase synthesis strategy by Ye group.However,challenges such as regioselectivity,stereoselectivity,reactivity control and steric hindrance continue to be obstacles in glycan synthesis.New glycosylation strategies,including the novel leaving groups such as thioimidate,glycosyl o-alkynylbenzoate(ABz),2-(2-propylsulfiinyl)benzyl(PSB)/S-2-(2-propylsulfinyl)benzyl(SPSP)and o-(p-methoxypheny-lethynyl)phenyl(MPEP)have been developed for the synthesis of glycan antigens from pathogen surface.These synthetic glycan epitopes are essential for understanding the importance of carbohydrates as targets for vaccines.
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