Total Syntheses of Conjugation‐Ready Repeating Units of Acinetobacter baumannii AB5075 for Glycoconjugate Vaccine Development

Abstract

Acinetobacter baumannii is an opportunistic pathogen that causes serious nosocomial infections. One of the multidrug-resistant strains, AB5075, can result in bacteremia, pneumonia and wound infections associated with high morbidity and mortality. The structurally unique glycans on the surface of these bacteria are attractive targets for the development of glycoconjugate vaccines. Here, we report the first total synthesis of the densely functionalized trisaccharide repeating unit of A. baumannii AB5075 as well as two analogues. The construction of 1,2-cis linkages between the rare sugars relies on a double-serial inversion strategy. The judicious selection of building blocks and reaction conditions allowed for stereoselective glycosylations, the installation of acetamido groups and the (S)-3-hydroxybutanoyl chain.

A Hitchhiker’s Guide to Problem Selection in Carbohydrate Synthesis

“…Indeed, the lab has developed several synthetic carbohydrate vaccine constructs that are either fully synthetic or produced through semisynthesis. These conjugates were active against a wide range of pathogens, including Acinetobacter baumannii , , Clostridium difficile , Klebsiella pneumoniae , and Streptococcus pneumoniae . − …”

Total Synthesis of a Pentasaccharide O‐Glycan from Acinetobacter baumannii

“…After 5 minutes, the reaction was allowed to warm to room temperature (18 °C). After 4 h, TLC showed total consumption of starting material 21 b and formation of a less polar spot (22). The reaction flask was transferred into an ice bath then quenched by dropwise addition of 3.0 mL MeOH followed by dropwise addition of water (7.0 mL) until gas evolution stopped.…”

“…However, the lack of the appropriate WaaL ligase gene in A. baumannii calls into question whether this was O ‐antigen or perhaps the repeating unit of a capsular polysaccharide [21] . In 2021, Zhang and Seeberger reported the synthesis of trisaccharide repeating units from the CPS of A. baumannii AB5075 [22] . In early 2022, we reported the synthesis of the tetrasaccharide CPS repeating unit from A. baumannii D78 [23] .…”

“…[21] In 2021, Zhang and Seeberger reported the synthesis of trisaccharide repeating units from the CPS of A. baumannii AB5075. [22] In early 2022, we reported the synthesis of the tetrasaccharide CPS repeating unit from A. baumannii D78. [23] Even more recently, Yang, Yin, and co-workers reported the synthesis and immunological evaluation of an LOS core structure from A. baumannii ATCC 17904.…”

Stereoselective Synthesis of the O‐antigen of A. baumannii ATCC 17961 Using Long‐Range Levulinoyl Group Participation

“…To date, more than 20 different A. baumannii polymeric saccharides have been elucidated among more than 90 serotypes [4] . In 2015, Nakamura reported the synthesis of the A. baumannii O18 tetrasaccharide; [5] in 2018, Wu disclosed the semi‐synthesis of a glyco‐conjugate vaccine of A. baumannii strain 54149 and found that pseudaminic acid (Pse) played a critical role in immunogenic activity; [6] in 2020, Gao demonstrated the synthesis of the A. baumannii K47 pentasaccharide using the α‐selective glycosylation method; [7] in 2021, Li and Chen described the synthesis of Pse‐CRM197 conjugates against A. baumannii Infection; [8] in the same year, Seeberger reported the synthesis of the trisaccharide repeating unit of A. baumannii AB5075; [9] one year later, Seeberger published an amazing work on synthetic carbohydrate‐based vaccines against A. baumannii 17978; [10] Yang and Yin reported the chemical synthesis and antigenic evaluation of inner core oligosaccharides of A. baumannii ; [11] recently, Sun described the synthesis of the tetrasaccharide subunit of A. baumannii SMAL, the nonasaccharide of the A. baumannii O22 and the tetrasaccharide fragment of A. baumannii ATCC 17961 [12] . The A. baumannii ATCC 17961 O‐antigen consists of pentasaccharide repeating unit (with core trisaccharide subunit [→6)‐β‐ d ‐Glc(1→3)‐β‐ d ‐GalNAc(1→3)‐α‐ d ‐Gal(1→], β‐linked to a 2,3‐diacetamido‐ d ‐glucuronate at C4‐OH of Gal and β‐linked GlcNAc at C6‐OH of Gal) (Figure 1).…”