Antivirulence Properties of a Low-Molecular-Weight Quaternized Chitosan Derivative against Pseudomonas aeruginosa

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.

Synthesis and study of antibiofilm and antivirulence properties of flavonol analogues generated by palladium catalyzed ligand free Suzuki–Miyaura coupling against Pseudomonas aeruginosa PAO1

“…All the cultures including the untreated control were incubated at 37 °C and OD was noted each 2 h starting from 0 h at 600 nm. 49 …”

Strategies to Promote the Journey of Nanoparticles Against Biofilm‐Associated Infections

“…To improve the therapeutic efficacy of antibiotics, the nanotechnology-based antimicrobials, as nanoparticles (NPs), had been explored and developed against biofilmassociated infections in the last dozen years. [14][15][16][17][18][19] Among them, several successful cases have been approved in clinic. For example, Arikayce, a liposomal inhaled formulation of amikacin, is used to treat pulmonary infections led by mycobacterium avium complex with biofilms.…”

Quorum quenching effect of cyclodextrins on the pyocyanin and pyoverdine production of Pseudomonas aeruginosa

“…In recent years, the exploration of repurposing existing pharmaceutical compounds for novel clinical indications has emerged as a significant focal point within the field of drug discovery (Baldelli et al 2020 ). The increasing rates of bacterial resistance to current antibiotics require innovative methods targeting bacterial virulence with potentially weaker selection for resistance than in the case of conventional antibiotics (Haque et al 2021 ; Maisetta et al 2021 ). Antibiotic-resistant Pseudomonas aeruginosa is an emerging clinical challenge (Conway et al 2003 ; Buzid et al 2016 ; Azam and Khan 2019 ) characterized by a broad spectrum of potential hosts and pathophysiological aspects of infection with a large arsenal of virulence factors and exoproducts, including elastase, hemolysin, rhamnolipids, pyocyanin, and pyoverdine (Lyczak et al 2000 ; Kang et al 2017 ).…”