Abstract
In primary ciliary dyskinesia (PCD) patients, Pseudomonas aeruginosa is a major opportunistic pathogen, frequently involved in chronic infections of the lower airways. Infections by this bacterial species correlates with a worsening clinical prognosis and recalcitrance to currently available therapeutics. The antimicrobial peptide, lin-SB056-1, in combination with the cation chelator ethylenediaminetetraacetic acid (EDTA), was previously demonstrated to be bactericidal against P. aeruginosa in an artificial sputum medium. The purpose of this study was to validate the anti-P. aeruginosa activity of such a combination in PCD sputum and to evaluate the in vitro anti-virulence effects of EDTA. In combination with EDTA, lin-SB056-1 was able to significantly reduce the load of endogenous P. aeruginosa ex vivo in the sputum of PCD patients. In addition, EDTA markedly reduced the production of relevant bacterial virulence factors (e.g., pyocyanin, proteases, LasA) in vitro by two representative mucoid strains of P. aeruginosa isolated from the sputum of PCD patients. These results indicate that the lin-SB056-1/EDTA combination may exert a dual antimicrobial and anti-virulence action against P. aeruginosa, suggesting a therapeutic potential against chronic airway infections sustained by this bacterium.
Highlights
Primary ciliary dyskinesia (PCD) is an autosomal recessive disorder characterized by abnormal ciliary ultrastructure and function leading to impaired mucociliary clearance and recurrent respiratory infections [1]
We have shown that the combination of lin-SB056-1/ethylenediaminetetraacetic acid (EDTA) possesses antimicrobial activity against P. aeruginosa in artificial sputum medium and prevents P. aeruginosa biofilm formation in an in vivo-like three-dimensional (3D) lung epithelial cell model [16,27]
In this study, we sought to validate the anti-pseudomonal activity of the lin-SB056-1/EDTA combination in conditions more closely resembling the environment found in vivo
Summary
Primary ciliary dyskinesia (PCD) is an autosomal recessive disorder characterized by abnormal ciliary ultrastructure and function leading to impaired mucociliary clearance and recurrent respiratory infections [1]. A negative correlation between the abundance of P. aeruginosa in the airways of these patients and lung function has been reported [2,3]. The pathogenesis of P. aeruginosa infection is at least partially attributable to its ability to synthesize and secrete a number of virulence factors (e.g., pyoverdine, pyocyanin, proteases) and to form biofilms, in which bacterial cells are embedded in an alginate extracellular matrix [4]. Once the patients are stably colonized by P. aeruginosa, the eradication of the bacterium is rarely achieved [1,5]. There is a critical need for novel antimicrobial drugs that can effectively lower P. aeruginosa load in the challenging environment of PCD lung
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