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

Dinu, Vlad; Lu, Yudong; Weston, Nicola; Lithgo, Ryan; Coupe, Hayley; Channell, Guy; Adams, Gary G; Torcello G�mez, Amelia; Sabater Sanchez, Carlos; Mackie, Alan; Parmenter, Christopher; Fisk, Ian; Phillips-Jones, Mary K.; Harding, Stephen E.

Abstract

© 2020, The Author(s). 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.

Citation

Dinu, V., Lu, Y., Weston, N., Lithgo, R., Coupe, H., Channell, G., Adams, G. G., Torcello Gómez, A., Sabater Sanchez, C., Mackie, A., Parmenter, C., Fisk, I., Phillips-Jones, M. K., & Harding, S. E. (2020). The antibiotic vancomycin induces complexation and aggregation of gastrointestinal and submaxillary mucins. Scientific Reports, 10(1), Article 960. https://doi.org/10.1038/s41598-020-57776-3

• Journal Article Type: Article
• Acceptance Date: Dec 19, 2019
• Online Publication Date: Jan 22, 2020
• Publication Date: Jan 22, 2020
• Deposit Date: Jan 8, 2020
• Publicly Available Date: Feb 25, 2020
• Journal: Scientific Reports
• Electronic ISSN: 2045-2322
• Publisher: Nature Publishing Group
• Peer Reviewed: Peer Reviewed
• Volume: 10
• Issue: 1
• Article Number: 960
• DOI: https://doi.org/10.1038/s41598-020-57776-3
• Keywords: Multidisciplinary
• Public URL: https://nottingham-repository.worktribe.com/output/3689964
• Publisher URL: https://www.nature.com/articles/s41598-020-57776-3
• Additional Information: Received: 29 May 2018; Accepted: 19 December 2019; First Online: 22 January 2020; : The authors declare no competing interests.