Limits...
Cysteamine (Lynovex®), a novel mucoactive antimicrobial & antibiofilm agent for the treatment of cystic fibrosis.

Charrier C, Rodger C, Robertson J, Kowalczuk A, Shand N, Fraser-Pitt D, Mercer D, O'Neil D - Orphanet J Rare Dis (2014)

Bottom Line: Any successful therapeutic strategy designed to combat the respiratory pathology of this condition must address the altered lung physiology and recurrent, complex, polymicrobial infections and biofilms that affect the CF pulmonary tract.In all cases, the 'gold standard' therapeutic agents were employed as control/comparator compounds against which the efficacy of cysteamine was compared.The data we present here provides a platform for cysteamine's continued investigation as a novel treatment for this poorly served orphan disease.

View Article: PubMed Central - PubMed

Affiliation: NovaBiotics Ltd, Cruickshank Building, Craibstone, Aberdeen, AB21 9TR, UK. cedric.charrier@gmail.com.

ABSTRACT

Background: There remains a critical need for more effective, safe, long-term treatments for cystic fibrosis (CF). Any successful therapeutic strategy designed to combat the respiratory pathology of this condition must address the altered lung physiology and recurrent, complex, polymicrobial infections and biofilms that affect the CF pulmonary tract. Cysteamine is a potential solution to these unmet medical needs and is described here for the first time as (Lynovex®) a single therapy with the potential to deliver mucoactive, antibiofilm and antibacterial properties; both in oral and inhaled delivery modes. Cysteamine is already established in clinical practice for an unrelated orphan condition, cystinosis, and is therefore being repurposed (in oral form) for cystic fibrosis from a platform of over twenty years of safety data and clinical experience.

Methods: The antibacterial and antibiofilm attributes of cysteamine were determined against type strain and clinical isolates of CF relevant pathogens using CLSI standard and adapted microbiological methods and a BioFlux microfluidic system. Assays were performed in standard nutrient media conditions, minimal media, to mimic the low metabolic activity of microbes/persister cells in the CF respiratory tract and in artificial sputum medium. In vivo antibacterial activity was determined in acute murine lung infection/cysteamine nebulisation models. The mucolytic potential of cysteamine was assessed against DNA and mucin in vitro by semi-quantitative macro-rheology. In all cases, the 'gold standard' therapeutic agents were employed as control/comparator compounds against which the efficacy of cysteamine was compared.

Results: Cysteamine demonstrated at least comparable mucolytic activity to currently available mucoactive agents. Cysteamine was rapidly bactericidal against both metabolically active and persister cells of Pseudomonas aeruginosa and also emerging CF pathogens; its activity was not sensitive to high ionic concentrations characteristic of the CF lung. Cysteamine prevented the formation of, and disrupted established P. aeruginosa biofilms. Cysteamine was synergistic with conventional CF antibiotics; reversing antibiotic resistance/insensitivity in CF bacterial pathogens.

Conclusions: The novel mucolytic-antimicrobial activity of cysteamine (Lynovex®) provides potential for a much needed new therapeutic strategy in cystic fibrosis. The data we present here provides a platform for cysteamine's continued investigation as a novel treatment for this poorly served orphan disease.

Show MeSH

Related in: MedlinePlus

Antibiofilm activity againstP. aeruginosaPAO1 Biofilms of A – cysteamine, N-Acetylcysteine, rhDNase and alginate lyase and B – cysteamine and cysteamine in combination with tobramycin. A- a: Untreated control; b: 1 mg/ml Cysteamine; c: 1 mg/ml N-acetylcysteine; d: 1 mg/ml Cysteamine hydrochloride; e: 1 mg/ml rhDNase I; f: 1 mg/ml Alginate lyase. B- a: Control 0 h; b: Control 16 h; c: 100 μg/ml cysteamine; d: 10 μg/ml tobramycin; e: 100 μg/ml cysteamine & 10 μg/ml tobramycin. In all cases, P. aeruginosa PAO1 biofilms were seeded, and their growth monitored, in the presence of the mucoactive and/or antibacterial compounds listed above for 16 h in the BioFlux200 microfluidic system at a flow rate of 0.5 Dyn/cm2.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
getmorefigures.php?uid=PMC4260250&req=5

Fig1: Antibiofilm activity againstP. aeruginosaPAO1 Biofilms of A – cysteamine, N-Acetylcysteine, rhDNase and alginate lyase and B – cysteamine and cysteamine in combination with tobramycin. A- a: Untreated control; b: 1 mg/ml Cysteamine; c: 1 mg/ml N-acetylcysteine; d: 1 mg/ml Cysteamine hydrochloride; e: 1 mg/ml rhDNase I; f: 1 mg/ml Alginate lyase. B- a: Control 0 h; b: Control 16 h; c: 100 μg/ml cysteamine; d: 10 μg/ml tobramycin; e: 100 μg/ml cysteamine & 10 μg/ml tobramycin. In all cases, P. aeruginosa PAO1 biofilms were seeded, and their growth monitored, in the presence of the mucoactive and/or antibacterial compounds listed above for 16 h in the BioFlux200 microfluidic system at a flow rate of 0.5 Dyn/cm2.

Mentions: The ability of cysteamine and cysteamine hydrochloride to prevent formation of P. aeruginosa PAO1 biofilms was compared with other mucoactive compounds currently used in clinical practice, or in development as a treatment for CF (rhDNAse I, alginate lyase and N-acetylecysteine) was determined using the Bioflux 200 microfluidic system. Cysteamine and cysteamine hydrochloride were effective in preventing P. aeruginosa biofilm formation (Figure 1A-b, 1A-d), as no microbial growth is seen, and superior to the other mucolytic agents tested; N-acetylcysteine (Figure 1A-c), rhDNase I (Figure 1A-e) and alginate lyase (Figure 1A-f), where biofilm formation is clearly evident, as also seen in the untreated control (Figure 1A-a).Figure 1


Cysteamine (Lynovex®), a novel mucoactive antimicrobial & antibiofilm agent for the treatment of cystic fibrosis.

Charrier C, Rodger C, Robertson J, Kowalczuk A, Shand N, Fraser-Pitt D, Mercer D, O'Neil D - Orphanet J Rare Dis (2014)

Antibiofilm activity againstP. aeruginosaPAO1 Biofilms of A – cysteamine, N-Acetylcysteine, rhDNase and alginate lyase and B – cysteamine and cysteamine in combination with tobramycin. A- a: Untreated control; b: 1 mg/ml Cysteamine; c: 1 mg/ml N-acetylcysteine; d: 1 mg/ml Cysteamine hydrochloride; e: 1 mg/ml rhDNase I; f: 1 mg/ml Alginate lyase. B- a: Control 0 h; b: Control 16 h; c: 100 μg/ml cysteamine; d: 10 μg/ml tobramycin; e: 100 μg/ml cysteamine & 10 μg/ml tobramycin. In all cases, P. aeruginosa PAO1 biofilms were seeded, and their growth monitored, in the presence of the mucoactive and/or antibacterial compounds listed above for 16 h in the BioFlux200 microfluidic system at a flow rate of 0.5 Dyn/cm2.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4260250&req=5

Fig1: Antibiofilm activity againstP. aeruginosaPAO1 Biofilms of A – cysteamine, N-Acetylcysteine, rhDNase and alginate lyase and B – cysteamine and cysteamine in combination with tobramycin. A- a: Untreated control; b: 1 mg/ml Cysteamine; c: 1 mg/ml N-acetylcysteine; d: 1 mg/ml Cysteamine hydrochloride; e: 1 mg/ml rhDNase I; f: 1 mg/ml Alginate lyase. B- a: Control 0 h; b: Control 16 h; c: 100 μg/ml cysteamine; d: 10 μg/ml tobramycin; e: 100 μg/ml cysteamine & 10 μg/ml tobramycin. In all cases, P. aeruginosa PAO1 biofilms were seeded, and their growth monitored, in the presence of the mucoactive and/or antibacterial compounds listed above for 16 h in the BioFlux200 microfluidic system at a flow rate of 0.5 Dyn/cm2.
Mentions: The ability of cysteamine and cysteamine hydrochloride to prevent formation of P. aeruginosa PAO1 biofilms was compared with other mucoactive compounds currently used in clinical practice, or in development as a treatment for CF (rhDNAse I, alginate lyase and N-acetylecysteine) was determined using the Bioflux 200 microfluidic system. Cysteamine and cysteamine hydrochloride were effective in preventing P. aeruginosa biofilm formation (Figure 1A-b, 1A-d), as no microbial growth is seen, and superior to the other mucolytic agents tested; N-acetylcysteine (Figure 1A-c), rhDNase I (Figure 1A-e) and alginate lyase (Figure 1A-f), where biofilm formation is clearly evident, as also seen in the untreated control (Figure 1A-a).Figure 1

Bottom Line: Any successful therapeutic strategy designed to combat the respiratory pathology of this condition must address the altered lung physiology and recurrent, complex, polymicrobial infections and biofilms that affect the CF pulmonary tract.In all cases, the 'gold standard' therapeutic agents were employed as control/comparator compounds against which the efficacy of cysteamine was compared.The data we present here provides a platform for cysteamine's continued investigation as a novel treatment for this poorly served orphan disease.

View Article: PubMed Central - PubMed

Affiliation: NovaBiotics Ltd, Cruickshank Building, Craibstone, Aberdeen, AB21 9TR, UK. cedric.charrier@gmail.com.

ABSTRACT

Background: There remains a critical need for more effective, safe, long-term treatments for cystic fibrosis (CF). Any successful therapeutic strategy designed to combat the respiratory pathology of this condition must address the altered lung physiology and recurrent, complex, polymicrobial infections and biofilms that affect the CF pulmonary tract. Cysteamine is a potential solution to these unmet medical needs and is described here for the first time as (Lynovex®) a single therapy with the potential to deliver mucoactive, antibiofilm and antibacterial properties; both in oral and inhaled delivery modes. Cysteamine is already established in clinical practice for an unrelated orphan condition, cystinosis, and is therefore being repurposed (in oral form) for cystic fibrosis from a platform of over twenty years of safety data and clinical experience.

Methods: The antibacterial and antibiofilm attributes of cysteamine were determined against type strain and clinical isolates of CF relevant pathogens using CLSI standard and adapted microbiological methods and a BioFlux microfluidic system. Assays were performed in standard nutrient media conditions, minimal media, to mimic the low metabolic activity of microbes/persister cells in the CF respiratory tract and in artificial sputum medium. In vivo antibacterial activity was determined in acute murine lung infection/cysteamine nebulisation models. The mucolytic potential of cysteamine was assessed against DNA and mucin in vitro by semi-quantitative macro-rheology. In all cases, the 'gold standard' therapeutic agents were employed as control/comparator compounds against which the efficacy of cysteamine was compared.

Results: Cysteamine demonstrated at least comparable mucolytic activity to currently available mucoactive agents. Cysteamine was rapidly bactericidal against both metabolically active and persister cells of Pseudomonas aeruginosa and also emerging CF pathogens; its activity was not sensitive to high ionic concentrations characteristic of the CF lung. Cysteamine prevented the formation of, and disrupted established P. aeruginosa biofilms. Cysteamine was synergistic with conventional CF antibiotics; reversing antibiotic resistance/insensitivity in CF bacterial pathogens.

Conclusions: The novel mucolytic-antimicrobial activity of cysteamine (Lynovex®) provides potential for a much needed new therapeutic strategy in cystic fibrosis. The data we present here provides a platform for cysteamine's continued investigation as a novel treatment for this poorly served orphan disease.

Show MeSH
Related in: MedlinePlus