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4-methoxybenzalacetone, the cinnamic acid analog as a potential quorum sensing inhibitor against Chromobacterium violaceum and Pseudomonas aeruginosa

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Abstract

The continuous increase in the incidence of infectious diseases and the rapid unchecked rise in multidrug-resistance to conventional antibiotics have led to the search for alternative strategies for treatment and clinical management of microbial infections. Since quorum sensing (QS) regulates numerous virulence determinants and pathogenicity in bacteria, inhibition of QS promises to be an attractive target for development of novel therapeutics. In this study, a series of cinnamic acid analogs and benzalacetone analogs were designed and synthesized, and their QS-inhibitory activities explored. We found that, among the test compounds, 4-methoxybenzalacetone (8) exhibited potent anti-quorum sensing property, as evidenced by inhibition of QS-controlled violacein production of Chromobacterium violaceum ATCC12472. The inhibitory activity of such a compound, which was the methyl keto analog of the corresponding cinnamic acid, was not only stronger than the parent cinnamic acid (1), but also superior to that of furanone, the reference drug. Based on our observations, its mechanism of quorum sensing inhibition is likely to be mediated by interference with N-acyl-homoserine lactones (AHL) synthesis. Moreover, 4-methoxybenzalacetone (8) also suppressed the production of pyocyanin, rhamnolipids and swarming motility of Pseudomonas aeruginosa, suggesting a broad spectrum of anti-QS activities of this compound. In terms of structure–activity relationship, the possible chemical substitutions on the scaffold of cinnamic acid required for QS inhibitory activity are also discussed. Since 4-methoxybenzalacetone (8) showed no toxicity to both bacteria and mammalian cells, our findings therefore indicate the anti-QS potential of this compound as a novel effective QS inhibitor.

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Data supporting this study is provided as supplementary material accompanying this paper.

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Funding

This work was supported by the National Research Council of Thailand through the Annual Research Fund of Naresuan University (Grant Number R2559B069). Supports from The Thailand Research Fund (DBG6180030) and the Center of Excellence for Innovation in Chemistry, Ministry of Higher Education, Science, Research, and Innovation are gratefully acknowledged.

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Authors and Affiliations

  1. Faculty of Medical Science, Department of Microbiology and Parasitology, Naresuan University, Phitsanulok, 65000, Thailand

    Pornpimon Jantaruk & Duangkamol Kunthalert

  2. Faculty of Science, Department of Chemistry and Center of Excellence for Innovation in Chemistry, Ramkhamhaeng University, Bangkok, 10240, Thailand

    Wachirachai Pabuprapap, Archawin Nakaew & Apichart Suksamrarn

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  1. Pornpimon Jantaruk
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  2. Wachirachai Pabuprapap
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  3. Archawin Nakaew
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  4. Duangkamol Kunthalert
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  5. Apichart Suksamrarn
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Contributions

Conceptualization: DK and AS; Methodology: PJ, WP, AN; Formal analysis and investigation: PJ, WP, AN; Writing—original draft preparation: PJ, DK and AS; Writing—review and editing: DK, WP and AS; Funding acquisition: DK and AS; Supervision: DK and AS.

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Correspondence to Duangkamol Kunthalert.

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Jantaruk, P., Pabuprapap, W., Nakaew, A. et al. 4-methoxybenzalacetone, the cinnamic acid analog as a potential quorum sensing inhibitor against Chromobacterium violaceum and Pseudomonas aeruginosa. World J Microbiol Biotechnol 37, 153 (2021). https://doi.org/10.1007/s11274-021-03119-x

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