Itaconimides as Novel Quorum Sensing Inhibitors of Pseudomonas aeroginosa

July Fong, Kim Thollund Mortensen, Amalie Nørskov, Katrine Qvortrup, Liang Yang, Choon Hong Tan, Thomas E. Nielsen, Michael Givskov*

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review

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Abstract

Pseudomonas aeruginosa is known as an opportunistic pathogen that often causes persistent infections associated with highly antibiotic-resistance and biofilms formation. Chemical interference with bacterial cell-cell communication, termed quorum sensing (QS), has been recognized as an attractive approach to control infections and address the drug resistance problems currently observed worldwide. Instead of imposing direct selective pressures on bacterial growth, the right bioactive compounds can preferentially block QS-based communication and attenuate cascades of bacterial gene expression and production of virulence factors, thus leading to reduced pathogenicity. Herein, we report on the potential of itaconimides as quorum sensing inhibitors (QSI) of P. aeruginosa. An initial hit was discovered in a screening program of an in-house compound collection, and subsequent structure-activity relationship (SAR) studies provided analogs that could reduce expression of central QS-regulated virulence factors
(elastase, rhamnolipid, and pyocyanin), and also successfully lead to the eradication of P. aeruginosa biofilms in combination with tobramycin. Further studies on the cytotoxicity of compounds using murine macrophages indicated no toxicity at common working concentrations, thereby pointing to the potential of these small molecules as promising entities for antimicrobial drug development.
Original languageEnglish
Article number443
JournalFrontiers in Cellular and Infection Microbiology
Volume8
Number of pages11
ISSN2235-2988
DOIs
Publication statusPublished - 2019

Keywords

  • Quorum sensing
  • Biofilm
  • Itaconimides
  • Antivirulence
  • Chemical biology

Cite this

Fong, July ; Mortensen, Kim Thollund ; Nørskov, Amalie ; Qvortrup, Katrine ; Yang, Liang ; Tan, Choon Hong ; Nielsen, Thomas E. ; Givskov, Michael. / Itaconimides as Novel Quorum Sensing Inhibitors of Pseudomonas aeroginosa. In: Frontiers in Cellular and Infection Microbiology. 2019 ; Vol. 8.
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abstract = "Pseudomonas aeruginosa is known as an opportunistic pathogen that often causes persistent infections associated with highly antibiotic-resistance and biofilms formation. Chemical interference with bacterial cell-cell communication, termed quorum sensing (QS), has been recognized as an attractive approach to control infections and address the drug resistance problems currently observed worldwide. Instead of imposing direct selective pressures on bacterial growth, the right bioactive compounds can preferentially block QS-based communication and attenuate cascades of bacterial gene expression and production of virulence factors, thus leading to reduced pathogenicity. Herein, we report on the potential of itaconimides as quorum sensing inhibitors (QSI) of P. aeruginosa. An initial hit was discovered in a screening program of an in-house compound collection, and subsequent structure-activity relationship (SAR) studies provided analogs that could reduce expression of central QS-regulated virulence factors(elastase, rhamnolipid, and pyocyanin), and also successfully lead to the eradication of P. aeruginosa biofilms in combination with tobramycin. Further studies on the cytotoxicity of compounds using murine macrophages indicated no toxicity at common working concentrations, thereby pointing to the potential of these small molecules as promising entities for antimicrobial drug development.",
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Itaconimides as Novel Quorum Sensing Inhibitors of Pseudomonas aeroginosa. / Fong, July; Mortensen, Kim Thollund; Nørskov, Amalie; Qvortrup, Katrine; Yang, Liang; Tan, Choon Hong; Nielsen, Thomas E.; Givskov, Michael.

In: Frontiers in Cellular and Infection Microbiology, Vol. 8, 443, 2019.

Research output: Contribution to journalJournal articleResearchpeer-review

TY - JOUR

T1 - Itaconimides as Novel Quorum Sensing Inhibitors of Pseudomonas aeroginosa

AU - Fong, July

AU - Mortensen, Kim Thollund

AU - Nørskov, Amalie

AU - Qvortrup, Katrine

AU - Yang, Liang

AU - Tan, Choon Hong

AU - Nielsen, Thomas E.

AU - Givskov, Michael

PY - 2019

Y1 - 2019

N2 - Pseudomonas aeruginosa is known as an opportunistic pathogen that often causes persistent infections associated with highly antibiotic-resistance and biofilms formation. Chemical interference with bacterial cell-cell communication, termed quorum sensing (QS), has been recognized as an attractive approach to control infections and address the drug resistance problems currently observed worldwide. Instead of imposing direct selective pressures on bacterial growth, the right bioactive compounds can preferentially block QS-based communication and attenuate cascades of bacterial gene expression and production of virulence factors, thus leading to reduced pathogenicity. Herein, we report on the potential of itaconimides as quorum sensing inhibitors (QSI) of P. aeruginosa. An initial hit was discovered in a screening program of an in-house compound collection, and subsequent structure-activity relationship (SAR) studies provided analogs that could reduce expression of central QS-regulated virulence factors(elastase, rhamnolipid, and pyocyanin), and also successfully lead to the eradication of P. aeruginosa biofilms in combination with tobramycin. Further studies on the cytotoxicity of compounds using murine macrophages indicated no toxicity at common working concentrations, thereby pointing to the potential of these small molecules as promising entities for antimicrobial drug development.

AB - Pseudomonas aeruginosa is known as an opportunistic pathogen that often causes persistent infections associated with highly antibiotic-resistance and biofilms formation. Chemical interference with bacterial cell-cell communication, termed quorum sensing (QS), has been recognized as an attractive approach to control infections and address the drug resistance problems currently observed worldwide. Instead of imposing direct selective pressures on bacterial growth, the right bioactive compounds can preferentially block QS-based communication and attenuate cascades of bacterial gene expression and production of virulence factors, thus leading to reduced pathogenicity. Herein, we report on the potential of itaconimides as quorum sensing inhibitors (QSI) of P. aeruginosa. An initial hit was discovered in a screening program of an in-house compound collection, and subsequent structure-activity relationship (SAR) studies provided analogs that could reduce expression of central QS-regulated virulence factors(elastase, rhamnolipid, and pyocyanin), and also successfully lead to the eradication of P. aeruginosa biofilms in combination with tobramycin. Further studies on the cytotoxicity of compounds using murine macrophages indicated no toxicity at common working concentrations, thereby pointing to the potential of these small molecules as promising entities for antimicrobial drug development.

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