Method: Initial studies modelled the interaction of the 10-15 Dpn oligosaccharides with mucin using molecular dynamic modelling. Scanning electron (SEM) and atomic force microscopy (AFM) were employed to study the physical interaction of alginate oligomers with mucin using both commercial (Sigma) and freshly isolated (porcine) mucin. Mucin-containing sputum samples were then isolated from cystic fibrosis patients who were carriers of multi drug resistant (MDR) Pseudomonas aeruginosa (n=10) with ethical approval. The ability of the oligomers to modify the gross physical, viscoelastic properties of diseased sputum samples (n=23) was then studied using conventional shear rheology. Samples were subjected to treatment with (i) OligoG (0.2-2%); (ii) distilled water control; (iii) 100 nM dornase alfa +/- OligoG (0.2-2%).
Result: Molecular dynamic (MD) simulations were utilised to study these interactions. Alterations in the structural assembly of mucin evident in SEM and AFM were witnessed in rheological analysis in the ability of OligoG to significantly decrease the elastic and viscous response of sputum at mucociliary clearance index (0.16 Hz, P< 0.0001) and cilia beat frequencies (10 Hz, P< 0.02). Furthermore, OligoG also significantly potentiated the effect of the mucolytic therapy dornase alfa (P< 0.01).
Conclusion: These studies highlight the potential utility of OligoG to disrupt mucin biopolymer interactions in both biofilms and biological fluids. These findings are of potential clinical significance in the management of MDR infections in ventilated patients following maxillofacial surgery and trauma. These agents are now undergoing Phase IIa human studies (supported by AlgiPharma AS).