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Synthesis and Evaluation of 3‑Deoxy‑d-manno-oct-2-ulosonic Acid Derivatives to Perturb Escherichia coli Lipopolysaccharide Biosynthesis

Z. S. Ziylan,Imke M. A. Bartels,Wahyu S. Widodo,J. V. van Dijl,Maximilian J. L. J. Fürst,D. Scheffers,M. Walvoort

Published 2025 in JACS Au

ABSTRACT

Lipopolysaccharides (LPS) play important roles in the Gram-negative bacterial cell envelope. LPS are located in the outer leaflet of the outer membrane and generally serve as the first defense layer against environmental stress. 3-Deoxy-d-manno-oct-2-ulosonic acid (Kdo) is a highly conserved monosaccharide that resides in the inner core region of LPS and that connects the lipid A moiety to the extending polysaccharide chain through the hydroxyl group on its C-5 position. Due to its central function in LPS, we hypothesized that metabolically incorporated Kdo derivatives modified on the C-5 position may impair LPS synthesis and therefore lead to a reduced outer membrane integrity. To test this, we successfully synthesized four Kdo derivatives, 5-epi-Kdo, 5-deoxy-Kdo, 5-epi-Kdo-8-N3, and 5-deoxy-Kdo-8-N3, and incubated Escherichia coli (E. coli) strains in the presence of these derivatives to investigate their influence on LPS production and labeling. Interestingly, while the 5-deoxy derivatives were not incorporated, 5-epi-Kdo-8-N3 was successfully incorporated in cell envelope-associated LPS and increased the sensitivity of the bacteria to vancomycin, indicating that 5-epi-Kdo-8-N3 incorporation in LPS interferes with outer membrane integrity.

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