Exploring the Scope of Functionalized N-Acylneuraminic Acid β-Methyl Glycosides as Inhibitors of Neisseria meningitidis CMP-Sialic Acid Synthetase

Cell surface sialylation is utilized by a number of pathogenic bacteria to evade the host immune system through molecular mimicry of host sialoglycoconjugates. Human pathogen <i>Neisseria meningitidis</i> serotype B (<i>Nm</i>B) expresses both sialylated capsule and surface lipooligosaccharides as pivotal virulence factors. An essential enzyme in the sialylation pathway of <i>Nm</i>B is CMP-sialic acid synthetase (CSS), which produces the activated nucleotide sugar necessary for sialic acid transfer. In this work, novel C-4, -5, -7, and -9 functionalized derivatives of neuraminic acid β-methyl glycoside (Neuβ2Me) were synthesized as candidate CSS inhibitors. A number of these were found to reduce the activity of <i>Nm</i>B CSS in vitro. The highest inhibition of <i>Nm</i>B CSS, in a mixed mode manner, was observed with a Neu5Acβ2Me C-9 serine carboxamide. Direct interaction with the enzyme was confirmed by Saturation Transfer Difference (STD) NMR. Supplementation of growth media with this compound reduced lipooligosaccharide (LOS) sialylation of living <i>N. meningitidis</i>, thus providing an interesting starting point for the development of specific <i>Nm</i>B CSS inhibitors as an alternative treatment strategy to fight bacterial infections.