Inhibitory effects of 4-hydroxy-2,5-dimethyl-3(2H)-furanone (HDMF) on acyl-homoserine lactone-mediated virulence factor production and biofilm formation in Pseudomonas aeruginosa PAO1

Abstract

4-Hydroxy-2,5-dimethyl-3(2H)-furanone (HDMF), a non-halogenated furanone found in a variety of fruits, has been shown to have antimicrobial activity. However, few studies have focused on its inhibitory effect on bacterial quorum sensing (QS) at levels below the non-inhibitory concentration. In this study, 0.1 μM HDMF decreased the production of QS signal molecules and inhibited QS-controlled biofilm formation by Pseudomonas aeruginosa PAO1 without causing growth inhibition. In the presence of 0.1 and 1.0 μM HDMF, biofilm production by PAO1 was reduced by 27.8 and 42.6%, respectively, compared to that by untreated control cells. HDMF (1.0 μM) also significantly affected virulence factor expression (regulated by the las, rhl, and pqs system), resulting in a significant reduction in the production of LasA protease (53.8%), rhamnolipid (40.9%), and pyocyanin (51.4%). This HDMF-dependent inhibition of virulence factor expression was overcome by increasing the levels of two QS signal molecules of P. aeruginosa, N-(3-oxo-dodecanoyl)-L-homoserine lactone and N-butyryl-L-homoserine lactone, suggesting reversible competitive inhibition between HDMF and these molecules. The results of this study indicate that HDMF has great potential as an inhibitor of QS, and that it may be of value as a therapeutic agent and in biofilm control, without increasing selective pressure for resistance development.

Quorum‐sensing inhibition abrogates the deleterious impact of Pseudomonas aeruginosa on airway epithelial repair

“…Several inhibitors of proteases and QS have been identified, and QS inhibitors have been proposed as adjuvant therapy to antibiotics (17)(18)(19)(20). Our data indicate that HDMF, which has been shown to restrain P. aeruginosa virulence production and biofilm formation (21), may also reduce the deleterious effect of P. aeruginosa on wound repair. However, such an approach with QSI should be adapted as a function of P. aeruginosa strains, as it may be inefficient in patients who are colonized by QS gene mutants.…”

“…Identification of exoproducts under lasR control that are responsible for the damaging action of P. aeruginosa on epithelial repair prompted us to assess the efficiency of HDMF, which is known to significantly decrease the production of QS signal molecules (21). We first confirmed that the elastase activity in PsaDM from the PAO1 strain grown in presence of HDMF was strongly reduced (;70%; Fig.…”

“…Single colonies were inoculated into lysogeny broth (LB) and grown under agitation at 250 RPM at 37°C. Where indicated, single colonies were grown into LB that was supplemented with 0.125 mg/ml HDMF (Sigma‐Aldrich), and viable bacteria counts were determined by standard microdilution and colony forming units plate counting (21). Planktonic bacterial cultures at stationary phase after 72 h of growth were then centrifuged at 7200 g for 10 min at room temperature.…”

“…Within libraries of natural and chemical compounds as well as U.S. Food and Drug Administration-approved drugs, several QSI have recently been identified (16)(17)(18)(19)(20). Among them, 4-hydroxy-2,5-dimethyl-3(2H )-furanone (HDMF; also known as furaneol or strawberry furanone) has been reported to inhibit virulence factors production and biofilm formation in P. aeruginosa without affecting cell viability (21).…”

Inhibitory action of essential oils against proteases activity of Paenibacillus larvae, the etiological agent of American Foulbrood disease

“…In many bacteria, the production of extracellular hydrolytic enzymes (including proteases) is regulated by QS (Novick et al, 1993;Choi et al, 2014;Tran et al, 2014;Weng et al, 2014). This signalling mechanism is mediated by molecules called autoinducers that accumulate in the external medium as the culture reaches a high cell density.…”