TY - JOUR
T1 - Disulfide Bond-Containing Ajoene Analogues As Novel Quorum Sensing Inhibitors of Pseudomonas aeruginosa
AU - Fong, July
AU - Yuan, Mingjun
AU - Jakobsen, Tim Holm
AU - Mortensen, Kim T.
AU - Delos Santos, May Margarette Salido
AU - Chua, Song Lin
AU - Yang, Liang
AU - Tan, Choon Hong
AU - Nielsen, Thomas E.
AU - Givskov, Michael
N1 - Funding Information:
This research was supported by the National Research Foundation and the Ministry of Education of Singapore under its Research Centre of Excellence Programme, the Start-up Grant (M4330002.C70) from Nanyang Technological University, and AcRF Tier 2 (MOE2014-T2-2-172) from Ministry of Education, Singapore.
Publisher Copyright:
© 2016 American Chemical Society.
PY - 2017/1/12
Y1 - 2017/1/12
N2 - Since its discovery 22 years ago, the bacterial cell-to-cell communication system, termed quorum sensing (QS), has shown potential as antipathogenic target. Previous studies reported that ajoene from garlic inhibits QS in opportunistic human pathogen Pseudomonas aeruginosa. In this study, screening of an in-house compound library revealed two sulfur-containing compounds which possess structural resemblance with ajoene and inhibit QS in bioreporter assay. Following a quantitative structure-activity relationship (SAR) study, 25 disulfide bond-containing analogues were synthesized and tested for QS inhibition activities. SAR study indicated that the allyl group could be replaced with other substituents, with the most active being benzothiazole derivative (IC50 = 0.56 μM). The compounds were able to reduce QS-regulated virulence factors (elastase, rhamnolipid, and pyocyanin) and successfully inhibit P. aeruginosa infection in murine model of implant-associated infection. Altogether, the QS inhibition activity of the synthesized compounds is encouraging for further exploration of novel analogues in antimicrobial drug development.
AB - Since its discovery 22 years ago, the bacterial cell-to-cell communication system, termed quorum sensing (QS), has shown potential as antipathogenic target. Previous studies reported that ajoene from garlic inhibits QS in opportunistic human pathogen Pseudomonas aeruginosa. In this study, screening of an in-house compound library revealed two sulfur-containing compounds which possess structural resemblance with ajoene and inhibit QS in bioreporter assay. Following a quantitative structure-activity relationship (SAR) study, 25 disulfide bond-containing analogues were synthesized and tested for QS inhibition activities. SAR study indicated that the allyl group could be replaced with other substituents, with the most active being benzothiazole derivative (IC50 = 0.56 μM). The compounds were able to reduce QS-regulated virulence factors (elastase, rhamnolipid, and pyocyanin) and successfully inhibit P. aeruginosa infection in murine model of implant-associated infection. Altogether, the QS inhibition activity of the synthesized compounds is encouraging for further exploration of novel analogues in antimicrobial drug development.
UR - http://www.scopus.com/inward/record.url?scp=85018473138&partnerID=8YFLogxK
U2 - 10.1021/acs.jmedchem.6b01025
DO - 10.1021/acs.jmedchem.6b01025
M3 - Journal article
C2 - 27977197
AN - SCOPUS:85018473138
SN - 0022-2623
VL - 60
SP - 215
EP - 227
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 1
ER -