Abstract
N-Acylhomoserine lactone (AHL)-mediated quorum-sensing (QS) regulates virulence functions in plant and animal pathogens such as Agrobacterium tumefaciens and Pseudomonas aeruginosa. A chemolibrary of more than 3500 compounds was screened using two bacterial AHL-biosensors to identify QS-inhibitors (QSIs). The purity and structure of 15 QSIs selected through this screening were verified using HPLC MS/MS tools and their activity tested on the A. tumefaciens and P. aeruginosa bacterial models. The IC50 value of the identified QSIs ranged from 2.5 to 90 µg/ml, values that are in the same range as those reported for the previously identified QSI 4-nitropyridine-N-oxide (IC50 24 µg/ml). Under the tested culture conditions, most of the identified QSIs did not exhibit bacteriostatic or bactericidal activities. One third of the tested QSIs, including the plant compound hordenine and the human sexual hormone estrone, decreased the frequency of the QS-regulated horizontal transfer of the tumor-inducing (Ti) plasmid in A. tumefaciens. Hordenine, estrone as well as its structural relatives estriol and estradiol, also decreased AHL accumulation and the expression of six QS-regulated genes (lasI, lasR, lasB, rhlI, rhlR, and rhlA) in cultures of the opportunist pathogen P. aeruginosa. Moreover, the ectopic expression of the AHL-receptors RhlR and LasR of P. aeruginosa in E. coli showed that their gene-regulatory activity was affected by the QSIs. Finally, modeling of the structural interactions between the human hormones and AHL-receptors LasR of P. aeruginosa and TraR of A. tumefaciens confirmed the competitive binding capability of the human sexual hormones. This work indicates potential interferences between bacterial and eukaryotic hormonal communications.
Highlights
Bacterial populations synthesize and exchange chemical signals which coordinate and synchronize gene expression in a celldensity dependent manner
Using C. violaceum CV026 in association with hexanoylhomoserine lactone (C6-HSL) at 0.5 mM and the tested compounds at 50 mg/ml, over 150 potential QS inhibitors (QSIs) corresponding to ca. 5% of the chemical library compounds, were identified
To improve the selectivity of the screening, we reduced the concentration of the tested compounds to 5 mg/ml and used the A. tumefaciens biosensor which is sensitive to very low amounts (10 nM) of octanoylhomoserine lactone (C8-HSL)
Summary
Bacterial populations synthesize and exchange chemical signals which coordinate and synchronize gene expression in a celldensity dependent manner. Such regulatory pathways are called quorum-sensing (QS) and involve diverse QS-signals, including Nacylhomoserine lactones (AHLs) [1]. Natural and synthetic compounds which alter QS signalling and thereby disrupt QS-regulated gene expression are called QS inhibitors (QSIs). The natural QSIs contribute to host defense against bacteria and both natural and synthetic QSIs have been proposed as promising molecules because they may act synergistically with antibiotics to limit bacterial infection [6,7,8]
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