Abstract
The co-occurrence of increasing rates of resistance to current antibiotics and the paucity of novel antibiotics pose major challenges for the treatment of bacterial infections. In this scenario, treatments targeting bacterial virulence have gained considerable interest as they are expected to exert a weaker selection for resistance than conventional antibiotics. In a previous study, we demonstrated that a low-molecular-weight quaternized chitosan derivative, named QAL, displays antibiofilm activity against the major pathogen Pseudomonas aeruginosa at subinhibitory concentrations. The aim of this study was to investigate whether QAL was able to inhibit the production of relevant virulence factors of P. aeruginosa. When tested in vitro at subinhibiting concentrations (0.31–0.62 mg/mL), QAL markedly reduced the production of pyocyanin, pyoverdin, proteases, and LasA, as well as inhibited the swarming motility of three out of four P. aeruginosa strains tested. Furthermore, quantitative reverse transcription PCR (qRT-PCR) analyses demonstrated that expression of lasI and rhlI, two QS-related genes, was highly downregulated in a representative P. aeruginosa strain. Confocal scanning laser microscopy analysis suggested that FITC-labelled QAL accumulates intracellularly following incubation with P. aeruginosa. In contrast, the reduced production of virulence factors was not evidenced when QAL was used as the main polymeric component of polyelectrolyte-based nanoparticles. Additionally, combination of sub-MIC concentrations of QAL and tobramycin significantly reduced biofilm formation of P. aeruginosa, likely due to a synergistic activity towards planktonic bacteria. Overall, the results obtained demonstrated an antivirulence activity of QAL, possibly due to polymer intracellular localization and QS-inhibition, and its ability to inhibit P. aeruginosa growth synergizing with tobramycin.
Highlights
A strong correlation has been reported between pyoverdine production by P. aeruginosa strains isolated from cystic fibrosis (CF) patients and virulence in the Caenorhabditis elegans model, with pyoverdine inhibitors significantly improving survival of the worms [41]
In the era of antimicrobial resistance, antivirulence strategies have been endorsed as an attractive approach to control bacterial infections
We evaluated the antibacterial and antibiofilm properties of quaternized Chitosan-derivatives designed to overcome the water solubility limitation of Chitosan and improve its intrinsic antimicrobial activity [18]
Summary
Pseudomonas aeruginosa is an opportunistic Gram-negative bacterium and a leading cause of nosocomial infections, highly contributing to morbidity and mortality of patients with cystic fibrosis (CF) or with severe burns [1,2,3]. P. aeruginosa readily acquires antimicrobial resistance determinants, resulting in multidrug-resistant or even pan-drug-resistant strains. The World Health Organization placed P. aeruginosa on the top of the priority pathogen list for the development of new antibiotics [4]. The ability of P. aeruginosa to colonize different human body districts and to resist both the host immune response and antimicrobial therapy mainly relies on its capacity to finely
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