The antibiotic vancomycin induces complexation and aggregation of gastrointestinal and submaxillary mucins

• Published in: Scientific reports Vol. 10; no. 1; p. 960
• Main Authors: Dinu, Vlad, Lu, Yudong, Weston, Nicola, Lithgo, Ryan, Coupe, Hayley, Channell, Guy, Adams, Gary G., Torcello Gómez, Amelia, Sabater, Carlos, Mackie, Alan, Parmenter, Christopher, Fisk, Ian, Phillips-Jones, Mary K., Harding, Stephen E.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 22-01-2020; Nature Publishing Group
• Subjects: 631/45/72/1202; 692/699/255/1318; Animals; Anti-Bacterial Agents - pharmacology; Antibiotic resistance; Antibiotics; Bacteria; Bioavailability; Cattle; Colonization; Development strategies; Enterocolitis; Gastrointestinal tract; Gastrointestinal Tract - drug effects; Gastrointestinal Tract - metabolism; Glycopeptides; Glycosylation; Gram-positive bacteria; Humanities and Social Sciences; Intestine; Light scattering; Macromolecules; Mucin; Mucins; Mucins - metabolism; Mucus; multidisciplinary; Protein Aggregates - drug effects; Protein Binding - drug effects; Scanning electron microscopy; Science; Science (multidisciplinary); Sedimentation; Swine; Ultracentrifugation; Vancomycin; Vancomycin - pharmacology
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-020-57776-3

Vancomycin, a branched tricyclic glycosylated peptide antibiotic, is a last-line defence against serious infections caused by staphylococci, enterococci and other Gram-positive bacteria. Orally-administered vancomycin is the drug of choice to treat pseudomembranous enterocolitis in the gastrointestinal tract. However, the risk of vancomycin-resistant enterococcal infection or colonization is significantly associated with oral vancomycin. Using the powerful matrix-free assay of co-sedimentation analytical ultracentrifugation, reinforced by dynamic light scattering and environmental scanning electron microscopy, and with porcine mucin as the model mucin system, this is the first study to demonstrate strong interactions between vancomycin and gastric and intestinal mucins, resulting in very large aggregates and depletion of macromolecular mucin and occurring at concentrations relevant to oral dosing. In the case of another mucin which has a much lower degree of glycosylation (~60%) – bovine submaxillary mucin - a weaker but still demonstrable interaction is observed. Our demonstration - for the first time - of complexation/depletion interactions for model mucin systems with vancomycin provides the basis for further study on the implications of complexation on glycopeptide transit in humans, antibiotic bioavailability for target inhibition,
in situ
generation of resistance and future development strategies for absorption of the antibiotic across the mucus barrier.