Itaconimides as Novel Quorum Sensing Inhibitors of Pseudomonas aeruginosa

Fong, July1; Mortensen, Kim T.2; Norskov, Amalie2; Qvortrup, Katrine2; Yang, Liang1,3; Tan, Choon Hong1,4; Nielsen, Thomas E.1,5; Givskov, Michael1,5

2019-01-07

10.3389/fcimb.2018.00443

Frontiers in Cellular and Infection Microbiology   影响因子和分区

2235-2988

Pseudomonas aeruginosa is known as an opportunistic pathogen that often causes persistent infections associated with high level of antibiotic-resistance and biofilms formation. Chemical interference with bacterial cell-to-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 pressure 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.

quorum sensing biofilm itaconimides antivirulence chemical biology

SCI

英语

通讯

Danish Council for Independent Research (FTP grant)[40616]

Immunology ; Microbiology

Immunology ; Microbiology

WOS:000455024800001

FRONTIERS MEDIA SA

Web of Science

1.Nanyang Technol Univ, Singapore Ctr Environm Life Sci Engn, Singapore, Singapore
2.Tech Univ Denmark, Dept Chem, Lyngby, Denmark
3.Southern Univ Sci & Technol, Shenzhen, Peoples R China
4.Nanyang Technol Univ, Sch Phys & Math Sci, Div Chem & Biol Chem, Singapore, Singapore
5.Univ Copenhagen, Costerton Biofilm Ctr, Dept Immunol & Microbiol, Copenhagen, Denmark

Fong, July,Mortensen, Kim T.,Norskov, Amalie,et al. Itaconimides as Novel Quorum Sensing Inhibitors of Pseudomonas aeruginosa[J]. Frontiers in Cellular and Infection Microbiology,2019,8.

Fong, July.,Mortensen, Kim T..,Norskov, Amalie.,Qvortrup, Katrine.,Yang, Liang.,...&Givskov, Michael.(2019).Itaconimides as Novel Quorum Sensing Inhibitors of Pseudomonas aeruginosa.Frontiers in Cellular and Infection Microbiology,8.

Fong, July,et al."Itaconimides as Novel Quorum Sensing Inhibitors of Pseudomonas aeruginosa".Frontiers in Cellular and Infection Microbiology 8(2019).