Abstract
Quorum sensing (QS) plays an important role during infection for the opportunistic human pathogen Pseudomonas aeruginosa. Quorum sensing inhibition (QSI) can disrupt this initial event of infection without killing bacterial cells, and thus QS inhibitors have been suggested as novel approaches for anti-infective therapy. Cinnamaldehyde (CAD) is a P. aeruginosa biofilm inhibitor and disperser of preformed biofilms. In this study, the combined use of CAD and colistin (COL) revealed a synergistic activity, but this was not the case for CAD combined with carbenicillin, tobramycin (TOB), or erythromycin in checkerboard assays for P. aeruginosa. CAD demonstrated QSI activity by repression of the expression of lasB, rhlA and pqsA in GFP reporter assays. Approximately 70% reduction in GFP production was observed with the highest CAD concentration tested in all the QS reporter strains. TOB also showed strong QSI when combined with CAD in reporter assays. Combination treatments revealed an additive activity of CAD with COL and TOB in biofilm inhibition (75.2% and 83.9%, respectively) and preformed biofilm dispersion (~90% for both) when compared to the individual treatments. Therefore, a proposed method to mitigate P. aeruginosa infection is a combination therapy of CAD with COL or CAD with TOB as alternatives to current individual drug therapies.
Highlights
The 20th century is recognized as the “antibiotic era”, which started with the discovery of antibiotics to fight bacterial infections
While the spread of antibiotic resistance is largely due to horizontal gene exchange or the acquisition of mutations associated with resistance, it is increasingly recognized that bacteria can exhibit increased tolerance to antimicrobials when they grow as a biofilm [2,3]
The role of biofilms in forming chronic, drug-tolerant infections is well known for Pseudomonas aeruginosa, which is one of the most studied pathogens for antimicrobial research according to the Infectious Diseases Society of America (IDSA) [6,7]
Summary
The 20th century is recognized as the “antibiotic era”, which started with the discovery of antibiotics to fight bacterial infections This has been marred by the emergence of multidrug-resistant bacteria [1] which has diminished the efficacy of antibiotic treatments. The QS system of P. aeruginosa is comprised of three hierarchically integrated QS systems, Las, Rhl and PQS, to control the expression of these virulence factors and biofilm genes that contribute to its pathogenicity [9]. One emerging strategy for supplementing the existing antibiotic treatment options is through the disruption of QS to inhibit virulence factor expression instead of inhibiting growth [10,11]. A previous study with sublethal concentrations of CAD demonstrated inhibition of QS virulence factors and biofilm formation in P. fluorescence [27]. We have exploited a combined positive effect of CAD and TOB on P. aeruginosa QS systems
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