Isoprenyl caffeate, a major compound in manuka propolis, is a quorum-sensing inhibitor in Chromobacterium violaceum
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The emergence of antibiotic-resistant bacterial pathogens, especially Gram-negative bacteria, has driven investigations into suppressing bacterial virulence via quorum sensing (QS) inhibition strategies instead of bactericidal and bacteriostatic approaches. Here, we investigated several bee products for potential compound(s) that exhibit significant QS inhibitory (QSI) properties at the phenotypic and molecular levels in Chromobacterium violaceum ATCC 12472 as a model organism. Manuka propolis produced the strongest violacein inhibition on C. violaceum lawn agar, while bee pollen had no detectable QSI activity and honey had bactericidal activity. Fractionated manuka propolis (pooled fraction 5 or PF5) exhibited the largest violacein inhibition zone (24.5 ± 2.5 mm) at 1 mg dry weight per disc. In C. violaceum liquid cultures, at least 450 µg/ml of manuka propolis PF5 completely inhibited violacein production. Gene expression studies of the vioABCDE operon, involved in violacein biosynthesis, showed significant (≥two-fold) down-regulation of vioA, vioD and vioE in response to manuka propolis PF5. A potential QSI compound identified in manuka propolis PF5 is a hydroxycinnamic acid-derivative, isoprenyl caffeate, with a [M−H] of 247. Complete violacein inhibition in C. violaceum liquid cultures was achieved with at least 50 µg/ml of commercial isoprenyl caffeate. In silico docking experiments suggest that isoprenyl caffeate may act as an inhibitor of the violacein biosynthetic pathway by acting as a competitor for the FAD-binding pockets of VioD and VioA. Further studies on these compounds are warranted toward the development of anti-pathogenic drugs as adjuvants to conventional antibiotic treatments, especially in antibiotic-resistant bacterial infections.
KeywordsQuorum sensing inhibition Manuka propolis Isoprenyl caffeate vio operon Antibiotic resistance Chromobacterium violaceum
This work was done with funding from UCSI University’s Faculty of Applied Sciences and the MAKNA Cancer Research Award 2012. We thank Prof. Tom Coenye for his constructive comments of the early findings of this study and helpful insights into the QSI activity of cinnamaldehyde and cinnamaldehyde derivatives. We also thank the Drug Design & Development Research Group (DDDRG) of the University of Malaya for use of the docking software.
Conflict of interest
The authors declare that they have no conflict of interest.
- Brackman G, Defoirdt T, Miyamoto C, Bossier P, Van CS, Nelis H, Coenye T (2008) Cinnamaldehyde and cinnamaldehyde derivatives reduce virulence in Vibrio spp. by decreasing the DNA-binding activity of the quorum sensing response regulator LuxR. BMC Microbiol 8:149PubMedCentralPubMedCrossRefGoogle Scholar
- Hentzer M, Wu H, Andersen JB, Riedel K, Rasmussen TB, Bagge N, Kumar N, Schembri MA, Song Z, Kristoffersen P, Manefield M, Costerton JW, Molin S, Eberl L, Steinberg P, Kjelleberg S, Høiby N, Givskov M (2003) Attenuation of Pseudomonas aeruginosa virulence by quorum sensing inhibitors. EMBO J 22:3803–3815PubMedCentralPubMedCrossRefGoogle Scholar
- Lamberte LE, Cabrera EC, Rivera WL (2011) Activity of the ethanolic extract of propolis (EEP) as a potential inhibitor of quorum sensing-mediated pigment production in Chromobacterium violaceum and virulence factor production in Pseudomonas aeruginosa. Philipp Agric Sci 94:14–22Google Scholar
- Slama TG (2008) Gram-negative antibiotic resistance: there is a price to pay. Crit Care 12(Suppl 10):1–7Google Scholar
- Taganna JC, Rivera WL (2008) Epigallocatechin gallate from Camellia sinensis L. (Kuntze) is a potential quorum sensing inhibitor in Chromobacterium violaceum. Sci Diliman 20:24–30Google Scholar
- Taganna JC, Quanico JP, Perono RM, Amor EC, Rivera WL (2011) Tannin-rich fraction from Terminalia catappa inhibits quorum sensing (QS) in Chromobacterium violaceum and the QS-controlled biofilm maturation and LasA staphylolytic activity in Pseudomonas aeruginosa. J Ethnopharmacol 134:865–871PubMedCrossRefGoogle Scholar
- Wang R, Starkey M, Hazan R, Rahme LG (2012) Honey’s ability to counter bacterial infections arises from both bactericidal compounds and QS inhibition. Front Microbiol 2012:144Google Scholar