Cysteamine as a Future Intervention in Cystic Fibrosis Against Current and Emerging Pathogens: A Patient-based ex vivo Study Confirming its Antimicrobial and Mucoactive Potential in Sputum

Abstract

BackgroundCysteamine has recently been shown to have in vitro properties potentially therapeutically beneficial in cystic fibrosis (CF). In this study we investigated the antimicrobial and mucolytic activity of cysteamine against the complex biologic matrix of CF sputum.MethodsSputum samples were obtained from 23 CF adults. Sputum polymicrobial content after in vitro exposure to cysteamine and standard CF antibiotics was assessed after a single exposure and after 14 days low-dose exposure. The effect of cysteamine on sputum spinnbarkeit was assessed.FindingsCysteamine reduced sputum polymicrobial burden by 3 · 18 (95% CI 2 · 30–4 · 07, p < 0.001) log10 units after 24 h incubation. Combined cysteamine and tobramycin reduced polymicrobial burden by a further 3 · 75 (95% CI 2 · 63–5 · 07, p < 0 · 001) log10 units above that seen with tobramycin. Repeated low dosing with cysteamine reduced sputum polymicrobial load from day 10 onwards (p = 0.032). Cysteamine reduced CF sputum viscoelasticity, sputum spinnbarkeit cysteamine 11.1 mm/s (95% CI 3.95–18.2) vs DNAse 1.69 mm/s (95% CI 0.73–2.65), p = 0.016. Cysteamine was active against Mycobacterium abscessus as a monotherapy and also potentiated the effects of amikacin and azithromycin.ConclusionFurther investigation is required into the therapeutic potential of cysteamine in CF to treat emerging as well as established microbial pathogens and as a mucolytic agent.

N -Acetyl- l -Cysteine and Cysteamine as New Strategies against Mixed Biofilms of Nonencapsulated Streptococcus pneumoniae and Nontypeable Haemophilus influenzae

“…Cys is also an antioxidant and is licensed for use in nephropathic cystinosis (43). It has also been proposed as suitable for use in Huntington's and Parkinson's diseases, malaria, neuropsychiatric disorders (44), and CF (45)(46)(47). Cys also prevents the formation of, and disrupts already established, Pseudomonas aeruginosa and Enterococcus faecalis biofilms (45,48).…”

“…Cys also prevents the formation of, and disrupts already established, Pseudomonas aeruginosa and Enterococcus faecalis biofilms (45,48). NAC and Cys show antimicrobial activity against Gram-positive and Gram-negative pathogens, with MICs usually falling in the range of 500 to 5,000 g/ml (45,46,(49)(50)(51), although lower values have been reported for some bacteria (46,52). It is generally recognized that the mechanisms underlying the therapeutic and clinical applications of NAC (and Cys) are still unclear and, possibly, more complex than previously envisaged (53).…”

Efficacy of Rhesus Theta-Defensin-1 in Experimental Models of Pseudomonas aeruginosa Lung Infection and Inflammation

“…Treated samples were placed into a vertically positioned 2-ml graduated pipette and run under gravity. Quantification of sputum velocity (in millimeters per second) was calculated over a distance of 390 mm (63,64). This test is an indirect measure of sputum elasticity and adhesion (50,65).…”

Synthesis of diacylated γ-glutamyl-cysteamine prodrugs, and in vitro evaluation of their cytotoxicity and intracellular delivery of cysteamine

“…Cysteamine is also of interest for its potential in treating other diseases, such as Huntington's disease [11,12], cystic fibrosis [13][14][15], chronic kidney disease [16], and non-alcoholic fatty liver disease (NAFLD), including non-alcoholic steatohepatitis (NASH) [17]. A current clinical trial is evaluating the potential of Procysbi ® as a disease-modifying treatment for Huntington's disease.…”