Identity and effects of quorum-sensing inhibitors produced by Penicillium species

Abstract

Quorum sensing (QS) communication systems are thought to afford bacteria with a mechanism to strategically cause disease. One example is Pseudomonas aeruginosa, which infects immunocompromised individuals such as cystic fibrosis patients. The authors have previously documented that blockage of the QS systems not only attenuates Ps. aeruginosa but also renders biofilms highly susceptible to treatment with conventional antibiotics. Filamentous fungi produce a battery of secondary metabolites, some of which are already in clinical use as antimicrobial drugs. Fungi coexist with bacteria but lack active immune systems, so instead rely on chemical defence mechanisms. It was speculated that some of these secondary metabolites could interfere with bacterial QS communication. During a screening of 100 extracts from 50 Penicillium species, 33 were found to produce QS inhibitory (QSI) compounds. In two cases, patulin and penicillic acid were identified as being biologically active QSI compounds. Their effect on QS-controlled gene expression in Ps. aeruginosa was verified by DNA microarray transcriptomics. Similar to previously investigated QSI compounds, patulin was found to enhance biofilm susceptibility to tobramycin treatment. Ps. aeruginosa has developed QS-dependent mechanisms that block development of the oxidative burst in PMN neutrophils. Accordingly, when the bacteria were treated with either patulin or penicillic acid, the neutrophils became activated. In a mouse pulmonary infection model, Ps. aeruginosa was more rapidly cleared from the mice that were treated with patulin compared with the placebo group.

Screening for novel quorum-sensing inhibitors to interfere with the formation of Pseudomonas aeruginosa biofilm

“…It is likely that compound 5 (emodin) penetrated into the biofilm and interfered with bacterial intercellular communications, by which the QS system of P. aeruginosa was disturbed and repressed. Moreover, previous studies have found that QS-deficient P. aeruginosa has reduced tolerance to such antimicrobial compounds as tobramycin and H 2 O 2 (Bjarnsholt et al, 2005;Rasmussen et al, 2005b). In addition, the results also showed that compound 5 can inhibit formation of S. maltophilia biofilm (Fig.…”

Quorum sensing inhibitors: a bargain of effects

“…QSI compounds, on the other hand, block or destroy the LuxR homologue proteins, resulting in a lowered overall concentration; hence the genes that require higher concentrations are the ones that are more readily inhibited. The QS-controlled genes PA2591, PA2163 and PA2570 (pa1L) identified by Rasmussen et al (2005b) support this. DNA array analysis of wild-type P. aeruginosa treated with different QSIs revealed that none of the compounds affected expression of PA2591, whereas PA2163 was downregulated by two inhibitors, 4-NPO and PA.…”

Exploiting Quorum Sensing To Confuse Bacterial Pathogens

“…They utilize the V. fischeri LuxR or P. aeruginosa LasR and RhlR proteins as targets, whose activities can be assessed upon regulation of toxic gene products (phospholipase A or levansucrase) or reporter gene products (␤-galactosidase or green fluorescent protein). A clear demonstration of this system can be found in studies that tested 100 extracts from 50 species of Penicillium, finding that one-third of species produce QSI compounds, including penicillic acid and patulin (232). Staphylococcal AIP reporters that make use of genetic reporters, such as ␤-galactosidase fused to central virulence genes of the agr QS system, have also been developed, which have allowed, for example, the identification of trihydroxy methyl xanthones from fungal sources as inhibitors of AIP signaling (233).…”

“…As such, QSI may render cells more susceptible to a variety of antimicrobial compounds. Two studies have recently assessed this possibility using QSI compounds found from natural sources together with tobramycin, a drug reported to inhibit biofilm development of P. aeruginosa QS mu-tants (232,250). In P. aeruginosa foreign-body infection models in mice, it was demonstrated that combinatorial treatments of tobramycin with either the furanone C-30, ajoene (from garlic), or horseradish extracts (with the major QSI component being iberin) all exhibited synergistic inhibitory activities toward viable bacterial cell counts when treatments were provided soon after implantation.…”