Author: ["Lingbing Kong","Leon Harrington","Qiuhong Li","Stephen Cheley","Benjamin G. Davis","Hagan Bayley"]
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Abstract
Capsular polysaccharides form the outermost protective layer around many Gram-negative bacteria. Antibiotics aimed directly at weakening this layer are not yet available. In pathogenic Escherichia coli E69, a protein, Wza, forms a pore in the outer membrane that transports K30 capsular polysaccharide from its site of synthesis to the outside of the cell. This therefore represents a prospective antibiotic target. Here we test a variety of grommet-like mimics of K30 capsular polysaccharide on wild-type Wza and on mutant open forms of the pore by electrical recording in planar lipid bilayers. The most effective glycomimetic was the unnatural cyclic octasaccharide octakis(6-deoxy-6-amino)cyclomaltooctaose (am8γCD), which blocks the α-helix barrel of Wza, a site that is directly accessible from the external medium. This glycomimetic inhibited K30 polysaccharide transport in live E. coli E69. With the protective outer membrane disrupted, the bacteria can be recognized and killed by the human immune system. Capsular polysaccharides (CPS) enclose many pathogenic strains of Escherichia coli, protecting the bacteria from the host. Here, an extracellular blocker of Wza, a pore-forming protein that transports CPS to the cell surface, has been discovered by single-channel electrical recording. Treatment with the blocker exposes the bacterial cell surface and thereby facilitates killing by the human immune system. Cite this article
Kong, L., Harrington, L., Li, Q. et al. Single-molecule interrogation of a bacterial sugar transporter allows the discovery of an extracellular inhibitor. Nature Chem 5, 651–659 (2013). https://doi.org/10.1038/nchem.1695 