Mucin structural interactions with an alginate oligomer mucolytic in cystic fibrosis sputum

Pritchard, M. C.; Oakley, Juliette; Brilliant, Charles D.; Rye, Phil D.; Forton, Julian; Doull, Iolo; Ketchell, Ian; Hill, Katja E.; Thomas, David W.; Lewis, Paul D.

doi:10.1016/j.vibspec.2019.102932

Cited by 17 publications

(11 citation statements)

References 44 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In addition, potentiation of rhDNase I (a mucolytic used in the treatment of CF) was observed when used in conjunction with OligoG, showing statistically significant differences in both G′ and G″ [ 4 ]. Fourier-transform infrared spectroscopy analysis of CF sputum confirmed an interaction with mucin glycans that supports the changes in viscoelastic properties of CF sputum in the presence of OligoG [ 5 ]. Results of sputum rheology in a clinical phase 2A study of nebulised OligoG ( www.clinicaltrialsregister.eu EudraCT number: 2010-023090-19), as well as ex vivo studies [ 5 , 6 ], indicated that OligoG normalises mucus biophysical properties ( i.e.…”

Section: Introductionmentioning

confidence: 77%

“…Fourier-transform infrared spectroscopy analysis of CF sputum confirmed an interaction with mucin glycans that supports the changes in viscoelastic properties of CF sputum in the presence of OligoG [ 5 ]. Results of sputum rheology in a clinical phase 2A study of nebulised OligoG ( www.clinicaltrialsregister.eu EudraCT number: 2010-023090-19), as well as ex vivo studies [ 5 , 6 ], indicated that OligoG normalises mucus biophysical properties ( i.e. viscosity) without degradation or cleavage of polymers within CF mucus.…”

Section: Introductionmentioning

confidence: 77%

“…It is a low molecular weight alginate oligosaccharide derived from the stem of the brown seaweed, Laminaria hyperborea . OligoG has been shown in previous in vitro studies to alter the viscoelastic properties of mucin/alginate gels, mucin/DNA gels and CF sputum [ 3 , – 5 ]. Extensional and shear rheology analyses showed that OligoG treatment resulted in marked reductions in both elastic (G′) and viscous response (G′′) of CF sputum compared to controls and a significant reduction in the elastic response, G′, and viscous response, G′′ [ 4 ].…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Inhaled dry powder alginate oligosaccharide in cystic fibrosis: a randomised, double-blind, placebo-controlled, crossover phase 2b study

Koningsbruggen-Rietschel

Davies

Pressler

et al. 2020

ERJ Open Res

Self Cite

View full text Add to dashboard Cite

BackgroundOligoG is a low molecular-weight alginate oligosaccharide that improves the viscoelastic properties of cystic fibrosis (CF) mucus and disrupts biofilms, thereby potentiating the activity of antimicrobial agents. The efficacy of inhaled OligoG was evaluated in adult patients with CF.MethodsA randomised, double-blind, placebo-controlled multicentre crossover study was used to demonstrate safety and efficacy of inhaled dry powder OligoG. Subjects were randomly allocated to receive OligoG 1050 mg per day (10 capsules three times daily) or matching placebo for 28 days, with 28-day washout periods following each treatment period. The primary end-point was absolute change in percentage predicted forced expiratory volume in 1 s (FEV1) at the end of 28-day treatment. The intention-to-treat (ITT) population (n=65) was defined as randomised to treatment with at least one administration of study medication and post-dosing evaluation.ResultsIn this study, 90 adult subjects were screened and 65 were randomised. Statistically significant improvement in FEV1 was not observed in the ITT population. Adverse events included nasopharyngitis, cough and pulmonary exacerbation. The number and proportions of patients with adverse events and serious adverse events were similar between OligoG and placebo group.ConclusionsInhalation of OligoG-dry powder over 28 days was safe in adult CF subjects. Statistically significant improvement of FEV1 was not reached. The planned analyses did not indicate a significant treatment benefit with OligoG compared to placebo. Post hoc exploratory analyses showed subgroup results that indicate that further studies of OligoG in this patient population are justified.

show abstract

Section: Introductionmentioning

confidence: 77%

Section: Introductionmentioning

confidence: 77%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Inhaled dry powder alginate oligosaccharide in cystic fibrosis: a randomised, double-blind, placebo-controlled, crossover phase 2b study

Koningsbruggen-Rietschel

Davies

Pressler

et al. 2020

ERJ Open Res

Self Cite

View full text Add to dashboard Cite

show abstract

“…A four-fold increase in the MIC of colistin was also reported when the assay was conducted in AS medium instead of MH broth, thought to be caused by bacterial growth disruption, structural modifications of lipopolysaccharides or direct colistin–mucin interactions [ 24 ]. Although recent studies have demonstrated the ability of OligoG to bind mucin [ 51 ], conjugation of OligoG to colistin and polymyxin B did not affect the ability of the antibiotic to bind mucin or alter the effect of nutrient-deficient medium.…”

Section: Discussionmentioning

confidence: 99%

Bi-Functional Alginate Oligosaccharide–Polymyxin Conjugates for Improved Treatment of Multidrug-Resistant Gram-Negative Bacterial Infections

et al. 2020

Self Cite

View full text Add to dashboard Cite

The recent emergence of resistance to colistin, an antibiotic of last resort with dose-limiting toxicity, has highlighted the need for alternative approaches to combat infection. This study aimed to generate and characterise alginate oligosaccharide (“OligoG”)–polymyxin (polymyxin B and E (colistin)) conjugates to improve the effectiveness of these antibiotics. OligoG–polymyxin conjugates (amide- or ester-linked), with molecular weights of 5200–12,800 g/mol and antibiotic loading of 6.1–12.9% w/w, were reproducibly synthesised. In vitro inflammatory cytokine production (tumour necrosis factor alpha (TNFα) ELISA) and cytotoxicity (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) of colistin (2.2–9.3-fold) and polymyxin B (2.9–27.2-fold) were significantly decreased by OligoG conjugation. Antimicrobial susceptibility tests (minimum inhibitory concentration (MIC), growth curves) demonstrated similar antimicrobial efficacy of ester- and amide-linked conjugates to that of the parent antibiotic but with more sustained inhibition of bacterial growth. OligoG–polymyxin conjugates exhibited improved selectivity for Gram-negative bacteria in comparison to mammalian cells (approximately 2–4-fold). Both OligoG–colistin conjugates caused significant disruption of Pseudomonas aeruginosa biofilm formation and induced bacterial death (confocal laser scanning microscopy). When conjugates were tested in an in vitro “time-to-kill” (TTK) model using Acinetobacter baumannii, only ester-linked conjugates reduced viable bacterial counts (~2-fold) after 4 h. Bi-functional OligoG–polymyxin conjugates have potential therapeutic benefits in the treatment of multidrug-resistant (MDR) Gram-negative bacterial infections, directly reducing toxicity whilst retaining antimicrobial and antibiofilm activities.

show abstract

“…OligoG is prepared from L. hyperborea stipe alginate by hydrolysis and fractionation, resulting in a mixture of oligomers enriched in G residues (>85%) with an average degree of polymerization between 15 and 17 (DPn). OligoG has been demonstrated to interact with mucins having an impact on mucus rheology [ 19 , 20 , 21 , 22 , 23 ], and recent studies suggest that OligoG can mobilize stagnant CF mucus by a calcium chelating mechanism [ 24 ]. Furthermore, OligoG is able to reduce and disrupt biofilm formation of the important CF lung pathogen P. aeruginosa presumably by direct disruption of the extracellular matrix and indirectly by modulating quorum sensing pathways [ 25 , 26 , 27 ].…”

Section: Introductionmentioning

confidence: 99%

Exploiting Mannuronan C-5 Epimerases in Commercial Alginate Production

et al. 2020

Self Cite

View full text Add to dashboard Cite

Alginates are one of the major polysaccharide constituents of marine brown algae in commercial manufacturing. However, the content and composition of alginates differ according to the distinct parts of these macroalgae and have a direct impact on the concentration of guluronate and subsequent commercial value of the final product. The Azotobacter vinelandii mannuronan C-5 epimerases AlgE1 and AlgE4 were used to determine their potential value in tailoring the production of high guluronate low-molecular-weight alginates from two sources of high mannuronic acid alginates, the naturally occurring harvested brown algae (Ascophyllum nodosum, Durvillea potatorum, Laminaria hyperborea and Lessonia nigrescens) and a pure mannuronic acid alginate derived from fermented production of the mutant strain of Pseudomonas fluorescens NCIMB 10,525. The mannuronan C-5 epimerases used in this study increased the content of guluronate from 32% up to 81% in both the harvested seaweed and bacterial fermented alginate sources. The guluronate-rich alginate oligomers subsequently derived from these two different sources showed structural identity as determined by proton nuclear magnetic resonance (1H NMR), high-performance anion-exchange chromatography with pulsed amperometric detection (HPAEC-PAD) and size-exclusion chromatography with online multi-angle static laser light scattering (SEC-MALS). Functional identity was determined by minimum inhibitory concentration (MIC) assays with selected bacteria and antibiotics using the previously documented low-molecular-weight guluronate enriched alginate OligoG CF-5/20 as a comparator. The alginates produced using either source showed similar antibiotic potentiation effects to the drug candidate OligoG CF-5/20 currently in development as a mucolytic and anti-biofilm agent. These findings clearly illustrate the value of using epimerases to provide an alternative production route for novel low-molecular-weight alginates.

show abstract

Mucin structural interactions with an alginate oligomer mucolytic in cystic fibrosis sputum

Cited by 17 publications

References 44 publications

Inhaled dry powder alginate oligosaccharide in cystic fibrosis: a randomised, double-blind, placebo-controlled, crossover phase 2b study

Inhaled dry powder alginate oligosaccharide in cystic fibrosis: a randomised, double-blind, placebo-controlled, crossover phase 2b study

Bi-Functional Alginate Oligosaccharide–Polymyxin Conjugates for Improved Treatment of Multidrug-Resistant Gram-Negative Bacterial Infections

Exploiting Mannuronan C-5 Epimerases in Commercial Alginate Production

Contact Info

Product

Resources

About