Abstract
BackgroundThere 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.MethodsThe 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.ResultsCysteamine 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.ConclusionsThe 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s13023-014-0189-2) contains supplementary material, which is available to authorized users.
Highlights
There remains a critical need for more effective, safe, long-term treatments for cystic fibrosis (CF)
Antibiofilm activity of cysteamine 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 was determined using the Bioflux 200 microfluidic system
It should be pointed out that the biofilm inoculum was a much more cell-dense, exponential growth phase culture of P. aeruginosa PAO1 (OD625 ~ 0.7), not the usually applied Clinical and Laboratory Standards Institute (CLSI) inoculum of ~5 × 105 cfu/ml (OD625 < 0.1) [18], so both putative antibiofilm agents were being tested at levels significantly below their MIC100 value
Summary
There remains a critical need for more effective, safe, long-term treatments for cystic fibrosis (CF). Antibiotics, whether administered systemically or by inhalation, remain a mainstay of the cystic fibrosis therapy regimen [1]. The co-administration of mucolytic or osmotic agents (e.g. DNAase/pulmozyme®, N-acetylcysteine/Mucomyst® and mannitol/Bronchitol® [3]) to reduce mucus viscosity and elasticity [4] is intended to facilitate increased antibioticmicrobe contact. These therapies can improve the patient’s ability to expectorate. The need to develop more effective strategies for the resolution of mucus build up and the eradication of the respiratory pathogens that infect and colonise the respiratory tract in cystic fibrosis is acute
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