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Isoprenyl caffeate, a major compound in manuka propolis, is a quorum-sensing inhibitor in Chromobacterium violaceum

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Abstract

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.

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Acknowledgments

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.

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Author notes

  1. Adrian Tandhyka Gemiarto

    Present address: Comparative Genomics Centre, James Cook University, Molecular Sciences Bldg 21, Townsville, QLD, 4811, Australia

  2. Nathaniel Nyakaat Ninyio

    Present address: Department of Microbiology, Faculty of Science, Kaduna State University, P.M.B 2339, Tafawa Balewa Way, Kaduna, Kaduna State, Nigeria

Authors and Affiliations

  1. Department of Biotechnology, Faculty of Applied Sciences, UCSI University, No 1, Jalan Menara Gading, UCSI Heights, 56000, Cheras, Kuala Lumpur, Malaysia

    Adrian Tandhyka Gemiarto, Nathaniel Nyakaat Ninyio, Siew Wei Lee, Joko Logis & Crystale Siew Ying Lim

  2. Department of Food Science and Nutrition, Faculty of Applied Sciences, UCSI University, No 1, Jalan Menara Gading, UCSI Heights, 56000, Cheras, Kuala Lumpur, Malaysia

    Eric Wei Chiang Chan

  3. Faculty of Pharmaceutical Sciences, UCSI University, No 1, Jalan Menara Gading, UCSI Heights, 56000, Kuala Lumpur, Malaysia

    Ayesha Fatima

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  1. Adrian Tandhyka Gemiarto
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Correspondence to Crystale Siew Ying Lim.

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Gemiarto, A.T., Ninyio, N.N., Lee, S.W. et al. Isoprenyl caffeate, a major compound in manuka propolis, is a quorum-sensing inhibitor in Chromobacterium violaceum . Antonie van Leeuwenhoek 108, 491–504 (2015). https://doi.org/10.1007/s10482-015-0503-6

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