Evaluating the alginate oligosaccharide (OligoG) as a therapy for Burkholderia cepacia complex cystic fibrosis lung infection

Fischer, R.; Schwarz, C.; Weiser, Rebecca; Mahenthiralingam, Eshwar; Smerud, Knut; Meland, Nils; Flaten, Hugo; Rye, P.D.

doi:10.1016/j.jcf.2022.01.003

Cited by 10 publications

(4 citation statements)

References 30 publications

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“…The results shown in this and previous studies (Tøndervik et al, 2014;Pritchard et al, 2017), together with the excellent safety profile and high tolerability of OligoG proven through clinical trials, (NCT02157922; NCT02453789; Van Koningsbruggen-Rietschel et al, 2020;Fischer et al, 2022), clearly demonstrate the clinical utility of the combination treatment (OligoG/nystatin) to treat biofilm-related candidal infections, especially those on in-dwelling silicone devices such as voice box prostheses and catheters, as an aid to increase device lifespan and reduce the risk of nosocomial infections (Nobile and Johnson, 2015;Andes et al, 2012;Eix and Nett, 2020). This study also highlights the possible role of OligoG in more appropriate management of other candidal-related infections currently being treated with nystatin alone, such as topical treatments for mastitis (Douglas, 2021), skin infections, and oro-pharyngeal candidiasis (Kojic and Darouiche, 2004;Pappas et al, 2004;Pappas et al, 2016) and also the prophylaxis and treatment of surgical/trauma ICU patients (Giglio et al, 2012).…”

Section: Discussionsupporting

confidence: 65%

Alginate oligosaccharides enhance the antifungal activity of nystatin against candidal biofilms

Powell

Adams

Quoraishi

et al. 2023

Front. Cell. Infect. Microbiol.

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BackgroundThe increasing prevalence of invasive fungal infections in immuno-compromised patients is a considerable cause of morbidity and mortality. With the rapid emergence of antifungal resistance and an inadequate pipeline of new therapies, novel treatment strategies are now urgently required.MethodsThe antifungal activity of the alginate oligosaccharide OligoG in conjunction with nystatin was tested against a range of Candida spp. (C. albicans, C. glabrata, C. parapsilosis, C. auris, C. tropicalis and C. dubliniensis), in both planktonic and biofilm assays, to determine its potential clinical utility to enhance the treatment of candidal infections. The effect of OligoG (0-6%) ± nystatin on Candida spp. was examined in minimum inhibitory concentration (MIC) and growth curve assays. Antifungal effects of OligoG and nystatin treatment on biofilm formation and disruption were characterized using confocal laser scanning microscopy (CLSM), scanning electron microscopy (SEM) and ATP cellular viability assays. Effects on the cell membrane were determined using permeability assays and transmission electron microscopy (TEM).ResultsMIC and growth curve assays demonstrated the synergistic effects of OligoG (0-6%) with nystatin, resulting in an up to 32-fold reduction in MIC, and a significant reduction in the growth of C. parapsilosis and C. auris (minimum significant difference = 0.2 and 0.12 respectively). CLSM and SEM imaging demonstrated that the combination treatment of OligoG (4%) with nystatin (1 µg/ml) resulted in significant inhibition of candidal biofilm formation on glass and clinical grade silicone surfaces (p < 0.001), with increased cell death (p < 0.0001). The ATP biofilm disruption assay demonstrated a significant reduction in cell viability with OligoG (4%) alone and the combined OligoG/nystatin (MIC value) treatment (p < 0.04) for all Candida strains tested. TEM studies revealed the combined OligoG/nystatin treatment induced structural reorganization of the Candida cell membrane, with increased permeability when compared to the untreated control (p < 0.001).ConclusionsAntimicrobial synergy between OligoG and nystatin against Candida spp. highlights the potential utility of this combination therapy in the prevention and topical treatment of candidal biofilm infections, to overcome the inherent tolerance of biofilm structures to antifungal agents.

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Section: Discussionsupporting

confidence: 65%

Alginate oligosaccharides enhance the antifungal activity of nystatin against candidal biofilms

Powell

Adams

Quoraishi

et al. 2023

Front. Cell. Infect. Microbiol.

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“…Research into anti-virulence drugs is ongoing, with one study identifying two compounds, nitrofurazone and erythromycin estolate, that reduce the expression of PqsE, a QSSM implicated in virulence factor production and biofilm formation [109]. Antibiotic potentiators are also in development, with the potential to increase the efficacy of antibiotics against Bcc infections in PwCF [110]. Meanwhile, phage therapy is a rapidly emerging area of therapeutic interest with clinical success against some CF pathogens already reported [111].…”

Section: Opportunitiesmentioning

confidence: 99%

Challenges and opportunities in the development of novel antimicrobial therapeutics for cystic fibrosis

Barton

Frost

Fothergill

et al. 2022

Journal of Medical Microbiology

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Chronic respiratory infection is the primary driver of mortality in individuals with cystic fibrosis (CF). Existing drug screening models utilised in preclinical antimicrobial development are unable to mimic the complex CF respiratory environment. Consequently, antimicrobials showing promising activity in preclinical models often fail to translate through to clinical efficacy in people with CF. Model systems used in CF anti-infective drug discovery and development range from antimicrobial susceptibility testing in nutrient broth, through to 2D and 3D in vitro tissue culture systems and in vivo models. No single model fully recapitulates every key aspect of the CF lung. To improve the outcomes of people with CF (PwCF) it is necessary to develop a set of preclinical models that collectively recapitulate the CF respiratory environment to a high degree of accuracy. Models must be validated for their ability to mimic aspects of the CF lung and associated lung infection, through evaluation of biomarkers that can also be assessed following treatment in the clinic. This will give preclinical models greater predictive power for identification of antimicrobials with clinical efficacy. The landscape of CF is changing, with the advent of modulator therapies that correct the function of the CFTR protein, while antivirulence drugs and phage therapy are emerging alternative treatments to chronic infection. This review discusses the challenges faced in current antimicrobial development pipelines, including the advantages and disadvantages of current preclinical models and the impact of emerging treatments.

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“…For example, tobramycin exhibits reduced antibiotic action in sputum and does not disrupt the viscoelastic properties of P. aeruginosa biofilms grown in airway mucus [21,24,25]. It has been proposed that disruption of the biofilm matrix may potentiate antibiotic efficacy and improve the potential for clearance [25,26], which has previously been observed with the use of alginate oligosaccharides [27][28][29][30][31]. Enzymatic degradation of DNA in the matrix via DNase has also demonstrated synergistic bactericidal action when used in combination with antibiotics [26].…”

Section: Introductionmentioning

confidence: 98%

Combination treatment to improve mucociliary transport of Pseudomonas aeruginosa biofilms

Rouillard,

Esther,

Kissner

et al. 2024

PLoS ONE

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People with muco-obstructive pulmonary diseases such as cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD) often have acute or chronic respiratory infections that are difficult to treat due in part to the accumulation of hyperconcentrated mucus within the airway. Mucus accumulation and obstruction promote chronic inflammation and infection and reduce therapeutic efficacy. Bacterial aggregates in the form of biofilms exhibit increased resistance to mechanical stressors from the immune response (e.g., phagocytosis) and chemical treatments including antibiotics. Herein, combination treatments designed to disrupt the mechanical properties of biofilms and potentiate antibiotic efficacy are investigated against mucus-grown Pseudomonas aeruginosa biofilms and optimized to 1) alter biofilm viscoelastic properties, 2) increase mucociliary transport rates, and 3) reduce bacterial viability. A disulfide bond reducing agent (tris(2-carboxyethyl)phosphine, TCEP), a surfactant (NP40), a biopolymer (hyaluronic acid, HA), a DNA degradation enzyme (DNase), and an antibiotic (tobramycin) are tested in various combinations to maximize biofilm disruption. The viscoelastic properties of biofilms are quantified with particle tracking microrheology and transport rates are quantified in a mucociliary transport device comprised of fully differentiated primary human bronchial epithelial cells. The combination of the NP40 with hyaluronic acid and tobramycin was the most effective at increasing mucociliary transport rates, decreasing the viscoelastic properties of mucus, and reducing bacterial viability. Multimechanistic targeting of biofilm infections may ultimately result in improved clinical outcomes, and the results of this study may be translated into future in vivo infection models.

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Evaluating the alginate oligosaccharide (OligoG) as a therapy for Burkholderia cepacia complex cystic fibrosis lung infection

Cited by 10 publications

References 30 publications

Alginate oligosaccharides enhance the antifungal activity of nystatin against candidal biofilms

Alginate oligosaccharides enhance the antifungal activity of nystatin against candidal biofilms

Challenges and opportunities in the development of novel antimicrobial therapeutics for cystic fibrosis

Combination treatment to improve mucociliary transport of Pseudomonas aeruginosa biofilms

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