Abstract
To address the drug-resistance of bacterial pathogens without imposing a selective survival pressure, virulence and biofilms are highly attractive targets. Here, we show that terrein, which was isolated from Aspergillus terreus, reduced virulence factors (elastase, pyocyanin, and rhamnolipid) and biofilm formation via antagonizing quorum sensing (QS) receptors without affecting Pseudomonas aeruginosa cell growth. Additionally, the effects of terrein on the production of QS signaling molecules and expression of QS-related genes were verified. Interestingly, terrein also reduced intracellular 3,5-cyclic diguanylic acid (c-di-GMP) levels by decreasing the activity of a diguanylate cyclase (DGC). Importantly, the inhibition of c-di-GMP levels by terrein was reversed by exogenous QS ligands, suggesting a regulation of c-di-GMP levels by QS; this regulation was confirmed using P. aeruginosa QS mutants. This is the first report to demonstrate a connection between QS signaling and c-di-GMP metabolism in P. aeruginosa, and terrein was identified as the first dual inhibitor of QS and c-di-GMP signaling.
Highlights
Infections caused by multidrug-resistant (MDR) gram-negative bacteria are a growing problem[1]
To identify an inhibitor of virulence factor production, over 12,300 microbial extracts were screened and evaluated for their ability to inhibit the production of elastase by P. aeruginosa PAO1
Terrein inhibited the production of virulence factors, quorum sensing (QS) signaling molecules, and QS gene expression with similar activity in PA14 cells to that in PAO1 cells, while it reduced c-di-GMP levels with weaker activity in PA14 cells than in PAO1 cells (Figs S8 and S9)
Summary
Infections caused by multidrug-resistant (MDR) gram-negative bacteria are a growing problem[1]. Traditional approaches to combat bacterial infection are aimed at killing bacteria or preventing their growth These strategies and compounds impose substantial stress on the target bacterium, rapidly leading to resistance[3]. P. aeruginosa QS appears to participate in the development of biofilm architecture rather than the initiation of biofilm formation Another important signal in bacteria that allows for adaptation to different environments is the second messenger 3,5-cyclic diguanylic acid (c-di-GMP)[13,14]. Terrein reduced the production of virulence factors, such as elastase, pyocyanin, and rhamnolipid, as well as biofilm formation without bactericidal action. Terrein inhibited both QS and c-di-GMP signaling. We report the in vitro and in vivo anti-virulence and anti-biofilm activity of terrein against P. aeruginosa, as well as its inhibition of QS and c-di-GMP and connections between QS and c-di-GMP in P. aeruginosa
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