Impact of fluoroquinolones and aminoglycosides on P. aeruginosa virulence factor production and cytotoxicity

Abstract

The opportunistic pathogen Pseudomonas aeruginosa is one of leading causes of disability and mortality worldwide and the world health organisation has listed it with the highest priority for the need of new antimicrobial therapies. P. aeruginosa strains responsible for the poorest clinical outcomes express either ExoS or ExoU, which are injected into target host cells via the type III secretion system (T3SS). ExoS is a bifunctional cytotoxin that promotes intracellular survival of invasive P. aeruginosa by preventing targeting of the bacteria to acidified intracellular compartments. ExoU is a phospholipase which causes destruction of host cell plasma membranes, leading to acute tissue damage and bacterial dissemination. Fluoroquinolones are usually employed as a first line of therapy as they have been shown to be more active against P. aeruginosain vitro than other antimicrobial classes. Their overuse over the past decade, however, has resulted in the emergence of antibiotic resistance. In certain clinical situations, aminoglycosides have been shown to be more effective then fluoroquinolones, despite their reduced potency towards P. aeruginosa in vitro. In this study, we evaluated the effects of fluoroquinolones (moxifloxacin and ciprofloxacin) and aminoglycosides (tobramycin and gentamycin) on T3SS expression and toxicity, in corneal epithelial cell infection models. We discovered that tobramycin disrupted T3SS expression and reduced both ExoS and ExoU mediated cytotoxicity, protecting infected HCE-t cells at concentrations below the minimal inhibitory concentration (MIC). The fluoroquinolones moxifloxacin and ciprofloxacin, however, upregulated the T3SS and did not inhibit and may have increased the cytotoxic effects of ExoS and ExoU.

1H-Pyrrole-2,5-dicarboxylic acid, a quorum sensing inhibitor from one endophytic fungus in Areca catechu L., acts as antibiotic accelerant against Pseudomonas aeruginosa

“…Quorum sensing inhibitors (QSIs) can attenuate the production of virulence factors and inhibit biofilm formation of pathogens without affecting their growth, leading to avoidance of multidrug resistance, which has attracted extensive attention. Aminoglycosides and β-lactam agents are usually the first line to treat P. aeruginosa infections ( Foulkes et al., 2022 ; Tamma et al., 2022 ). Combined with aminoglycoside antibiotics, hordenine as a typical QSI could downregulate genes involved in QS and biofilm formation to enhance the susceptibility of aminoglycosides against P. aeruginosa PAO1 biofilm formation ( Zhou et al., 2018b ).…”

Pseudomonas aeruginosa ExoU-associated virulence in HCT recipients and patients with hematologic malignancies

“…If supported by such studies, strategies to rapidly detect exoU in P. aeruginosa isolates and to develop interventions to mitigate its impact 8 are justified. Intriguingly, tobramycin disrupted type-III secretion system expression and reduced ExoU-mediated cytotoxicity, 23 suggesting a potential role for adjunctive tobramycin targeted to the treatment of exoU + isolates. Because of the limitations inherent to our study and our institutional approach to tobramycin use in these patients, we were unable to evaluate the impact of tobramycin administration on the outcomes.…”