title: Cysteamine (Lynovex®), a novel mucoactive antimicrobial & antibiofilm agent for the treatment of cystic fibrosis.
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.
authors.affiliation: NovaBiotics Ltd, Cruickshank Building, Craibstone, Aberdeen, AB21 9TR, UK. cedric.charrier@gmail.com.
authors.forename: Cedric
authors.initials: C
authors.lastname: Charrier
authors.affiliation: NovaBiotics Ltd, Cruickshank Building, Craibstone, Aberdeen, AB21 9TR, UK. info@novabiotics.co.uk.
authors.forename: Catherine
authors.initials: C
authors.lastname: Rodger
authors.affiliation: NovaBiotics Ltd, Cruickshank Building, Craibstone, Aberdeen, AB21 9TR, UK. jennifer@novabiotics.co.uk.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Robertson
authors.affiliation: NovaBiotics Ltd, Cruickshank Building, Craibstone, Aberdeen, AB21 9TR, UK. aleksandra@novabiotics.co.uk.
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Kowalczuk
authors.affiliation: NovaBiotics Ltd, Cruickshank Building, Craibstone, Aberdeen, AB21 9TR, UK. info@novabiotics.co.uk.
authors.forename: Nicola
authors.initials: N
authors.lastname: Shand
authors.affiliation: NovaBiotics Ltd, Cruickshank Building, Craibstone, Aberdeen, AB21 9TR, UK. doug@novabiotics.co.uk.
authors.forename: Douglas
authors.initials: D
authors.lastname: Fraser-Pitt
authors.affiliation: NovaBiotics Ltd, Cruickshank Building, Craibstone, Aberdeen, AB21 9TR, UK. derry@novabiotics.co.uk.
authors.forename: Derry
authors.initials: D
authors.lastname: Mercer
authors.affiliation: NovaBiotics Ltd, Cruickshank Building, Craibstone, Aberdeen, AB21 9TR, UK. deborah@novabiotics.co.uk.
authors.forename: Deborah
authors.initials: D
authors.lastname: O'Neil
mesh_terms: D000818:Animals; D000890:Anti-Infective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D018441:Biofilms / Q000187:drug effects* / Q000254:growth & development; D003543:Cysteamine / Q000494:pharmacology* / Q000627:therapeutic use; D003550:Cystic Fibrosis / Q000188:drug therapy / Q000378:metabolism / Q000382:microbiology*; D005100:Expectorants / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D008826:Microbial Sensitivity Tests / Q000379:methods; D009077:Mucins / Q000378:metabolism*; D013552:Swine; D016896:Treatment Outcome
chemical_list: D000890:Anti-Infective Agents; D005100:Expectorants; D009077:Mucins; D003543:Cysteamine