Disruption of Quorum Sensing and Virulence in
            <i>Burkholderia cenocepacia</i>
            by a Structural Analogue of the
            <i>cis</i>
            -2-Dodecenoic Acid Signal

Cui, Chaoyu; Song, Shihao; Yang, Chunxi; Sun, Xiaoning; Huang, Yutong; Li, Kang; Zhao, Shuo; Zhang, Yongliang; Deng, Yinyue

doi:10.1128/aem.00105-19

Cited by 31 publications

(31 citation statements)

References 45 publications

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“…We initially focused our attention on B. cenocepacia CepIR because this QS system solely controls pathogenicity in C. elegans where the virulence attenuation of PAA degradation mutants was first characterized (22). However, current evidence suggests that a two-component system, RqpSR, is at the top of the hierarchy controlling both AHL-and Burkholderia diffusible signal factor (BDSF)-dependent QS systems (39,40). The BDSF-dependent system uses cis-2-dodecenoic acid signaling molecule (BDSF) that regulates overlapping genes with the AHL QS system (41).…”

Section: Discussionmentioning

confidence: 99%

Phenylacetyl Coenzyme A, Not Phenylacetic Acid, Attenuates CepIR-Regulated Virulence in Burkholderia cenocepacia

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Frejuk

Groleau

et al. 2019

Appl Environ Microbiol

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During phenylalanine catabolism, phenylacetic acid (PAA) is converted to phenylacetyl coenzyme A (PAA-CoA) by a ligase, PaaK, and then PAA-CoA is epoxidized by a multicomponent monooxygenase, PaaABCDE, before further degradation through the tricarboxylic acid (TCA) cycle. In the opportunistic pathogen Burkholderia cenocepacia, loss of paaABCDE attenuates virulence factor expression, which is under the control of the LuxIR-like quorum sensing (QS) system, CepIR. To further investigate the link between CepIR-regulated virulence and PAA catabolism, we created knockout mutants of the first step of the pathway (PAA-CoA synthesis by PaaK) and characterized them in comparison to a paaABCDE mutant using liquid chromatography-tandem mass spectrometry (LC-MS/MS) and virulence assays. We found that while loss of PaaABCDE decreased virulence, deletion of the paaK genes resulted in a more virulent phenotype than that of the wild-type strain. Deletion of either paaK or paaABCDE led to higher levels of released PAA but no differences in levels of internal accumulation compared to the wild-type level. While we found no evidence of direct cepIR downregulation by PAA-CoA or PAA, a low-virulence cepR mutant reverted to a virulent phenotype upon removal of the paaK genes. On the other hand, removal of paaABCDE in the cepR mutant did not impact its attenuated phenotype. Together, our results suggest an indirect role for PAA-CoA in suppressing B. cenocepacia CepIR-activated virulence. IMPORTANCE The opportunistic pathogen Burkholderia cenocepacia uses a chemical signal process called quorum sensing (QS) to produce virulence factors. In B. cenocepacia, QS relies on the presence of the transcriptional regulator CepR which, upon binding QS signal molecules, activates virulence. In this work, we found that even in the absence of CepR, B. cenocepacia can elicit a pathogenic response if phenylacetyl-CoA, an intermediate of the phenylacetic acid degradation pathway, is not produced. Instead, accumulation of phenylacetyl-CoA appears to attenuate pathogenicity. Therefore, we have discovered that it is possible to trigger virulence in the absence of CepR, challenging the classical view of activation of virulence by this QS mechanism. Our work provides new insight into the relationship between metabolism and virulence in opportunistic bacteria. We propose that in the event that QS signaling molecules cannot accumulate to trigger a pathogenic response, a metabolic signal can still activate virulence in B. cenocepacia.

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Section: Discussionmentioning

confidence: 99%

Phenylacetyl Coenzyme A, Not Phenylacetic Acid, Attenuates CepIR-Regulated Virulence in Burkholderia cenocepacia

Lightly

Frejuk

Groleau

et al. 2019

Appl Environ Microbiol

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“…Recently, several studies reported that fatty acids exhibit anti‐hyphal and antibiofilm activities at concentrations less than their MICs (Kumar et al ., 2020). For example, several fatty acids have been shown to selectively disrupt or inhibit biofilm formation by various microbial pathogens, such as Staphylococcus aureus (Davies and Marques, 2009; Kim et al ., 2018), Pseudomonas aeruginosa (Inoue et al ., 2008; Wenderska et al ., 2011), Candida albicans (Murzyn et al ., 2010; Muthamil et al ., 2018; Prasath et al ., 2019), and others (Wenderska et al ., 2011; Santhakumari et al ., 2017; Ramanathan et al ., 2018; Cui et al ., 2019). More specifically, capric acid (10:0) and lauric acid (12:0) inhibit the growth of planktonic Candida cells (Bergsson et al ., 2001), and butanoic acid (4:0) inhibit hyphal formation by C. albicans (Noverr and Huffnagle, 2004).…”

Section: Introductionmentioning

confidence: 99%

Antibiofilm and antifungal activities of medium‐chain fatty acids against Candida albicans via mimicking of the quorum‐sensing molecule farnesol

Lee

Kim

Khadke

2020

Microbial Biotechnology

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Candida biofilms are tolerant to conventional antifungal therapeutics and the host immune system. The transition of yeast cells to hyphae is considered a key step in C. albicans biofilm development, and this transition is inhibited by the quorum-sensing molecule farnesol. We hypothesized that fatty acids mimicking farnesol might influence hyphal and biofilm formation by C. albicans. Among 31 saturated and unsaturated fatty acids, six medium-chain saturated fatty acids, that is, heptanoic acid, octanoic acid, nonanoic acid, decanoic acid, undecanoic acid and lauric acid, effectively inhibited C. albicans biofilm formation by more than 75% at 2 µg ml À1 with MICs in the range 100-200 µg ml À1. These six fatty acids at 2 µg ml À1 and farnesol at 100 µg ml À1 inhibited hyphal growth and cell aggregation. The addition of fatty acids to C. albicans cultures decreased the productions of farnesol and sterols. Furthermore, downregulation of several hyphal and biofilm-related genes caused by heptanoic or nonanoic acid closely resembled the changes caused by farnesol. In addition, nonanoic acid, the most effective compound diminished C. albicans virulence in a Caenorhabditis elegans model. Our results suggest that mediumchain fatty acids inhibit more effectively hyphal growth and biofilm formation than farnesol.

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“…In Burkholderia cenocepacia , DSF diffuse across the membrane to bind to cytosolic proteins to activate transcriptional changes ( Suppiger et al, 2016 ). Cui et al (2019) developed a DSF analog that was capable of interfering with Burkholderia cenocepacia quorum sensing and virulence, demonstrating its potential as a novel antibacterial agent. Similarly, Huedo et al (2019) developed DSF that could interfere with quorum sensing of both Stenotrophomonas maltophilia and Burkholderia cepacia .…”

Section: Discussionmentioning

confidence: 99%

2-Heptylcyclopropane-1-Carboxylic Acid Disperses and Inhibits Bacterial Biofilms

et al. 2021

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Fatty-acid signaling molecules can inhibit biofilm formation, signal dispersal events, and revert dormant cells within biofilms to a metabolically active state. We synthesized 2-heptylcyclopropane-1-carboxylic acid (2CP), an analog of cis-2-decenoic acid (C2DA), which contains a cyclopropanated bond that may lock the signaling factor in an active state and prevent isomerization to its least active trans-configuration (T2DA). 2CP was compared to C2DA and T2DA for ability to disperse biofilms formed by Staphylococcus aureus and Pseudomonas aeruginosa. 2CP at 125 μg/ml dispersed approximately 100% of S. aureus cells compared to 25% for C2DA; both 2CP and C2DA had significantly less S. aureus biofilm remaining compared to T2DA, which achieved no significant dispersal. 2CP at 125 μg/ml dispersed approximately 60% of P. aeruginosa biofilms, whereas C2DA and T2DA at the same concentration dispersed 40%. When combined with antibiotics tobramycin, tetracycline, or levofloxacin, 2CP decreased the minimum concentration required for biofilm inhibition and eradication, demonstrating synergistic and additive responses for certain combinations. Furthermore, 2CP supported fibroblast viability above 80% for concentrations below 1 mg/ml. This study demonstrates that 2CP shows similar or improved efficacy in biofilm dispersion, inhibition, and eradication compared to C2DA and T2DA and thus may be promising for use in preventing infection for healthcare applications.

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Disruption of Quorum Sensing and Virulence in Burkholderia cenocepacia by a Structural Analogue of the cis -2-Dodecenoic Acid Signal

Cited by 31 publications

References 45 publications

Phenylacetyl Coenzyme A, Not Phenylacetic Acid, Attenuates CepIR-Regulated Virulence in Burkholderia cenocepacia

Phenylacetyl Coenzyme A, Not Phenylacetic Acid, Attenuates CepIR-Regulated Virulence in Burkholderia cenocepacia

Antibiofilm and antifungal activities of medium‐chain fatty acids against Candida albicans via mimicking of the quorum‐sensing molecule farnesol

2-Heptylcyclopropane-1-Carboxylic Acid Disperses and Inhibits Bacterial Biofilms

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