Abstract
Pseudomonas aeruginosa is a major opportunistic human pathogen which employs a myriad of virulence factors. In people with cystic fibrosis (CF) P. aeruginosa frequently colonises the lungs and becomes a chronic infection that evolves to become less virulent over time, but often adapts to favour persistence in the host with alginate-producing mucoid, slow-growing, and antibiotic resistant phenotypes emerging. Cysteamine is an endogenous aminothiol which has been shown to prevent biofilm formation, reduce phenazine production, and potentiate antibiotic activity against P. aeruginosa, and has been investigated in clinical trials as an adjunct therapy for pulmonary exacerbations of CF. Here we demonstrate (for the first time in a prokaryote) that cysteamine prevents glycine utilisation by P. aeruginosa in common with previously reported activity blocking the glycine cleavage system in human cells. Despite the clear inhibition of glycine metabolism, cysteamine also inhibits hydrogen cyanide (HCN) production by P. aeruginosa, suggesting a direct interference in the regulation of virulence factor synthesis. Cysteamine impaired chemotaxis, lowered pyocyanin, pyoverdine and exopolysaccharide production, and reduced the toxicity of P. aeruginosa secreted factors in a Galleria mellonella infection model. Thus, cysteamine has additional potent anti-virulence properties targeting P. aeruginosa, further supporting its therapeutic potential in CF and other infections.
Highlights
Pseudomonas aeruginosa is a versatile and opportunistic human pathogen and often recalcitrant to antibiotic therapy
This Gram negative motile rod-shaped bacterium was thought to be intrinsically resistant to macrolide antibiotics, though recent evidence suggests that the high minimal inhibitory concentrations (MICs) found in in vitro susceptibility testing media were less reflective of antimicrobial activity in physiological conditions (Buyck et al, 2012)
Pyoverdine is necessary for virulence in numerous infection models and chemical inhibitors of the production of this siderophore have demonstrated potential in mouse models of infection (Kang et al, 2019) we investigated the impact of cysteamine on pyoverdine fluorescence
Summary
Pseudomonas aeruginosa is a versatile and opportunistic human pathogen and often recalcitrant to antibiotic therapy. Despite recent falls in prevalence, it is still a common species found in the sputum of adults with CF (Cystic Fibrosis Foundation Patient Registry: 2018 Annual Data Report, 2019). This Gram negative motile rod-shaped bacterium was thought to be intrinsically resistant to macrolide antibiotics, though recent evidence suggests that the high minimal inhibitory concentrations (MICs) found in in vitro susceptibility testing media were less reflective of antimicrobial activity in physiological conditions (Buyck et al, 2012). The rising incidence of acquired resistance, to carbapenems has led to its designation as a critical priority pathogen of concern by WHO (World Health Organisation (WHO), 2017)
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