At a supra-physiological concentration, human sexual hormones act as quorum-sensing inhibitors

PLoS One. 2013 Dec 23;8(12):e83564. doi: 10.1371/journal.pone.0083564. eCollection 2013.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Agrobacterium tumefaciens / cytology
  • Agrobacterium tumefaciens / drug effects
  • Agrobacterium tumefaciens / genetics
  • Bacterial Proteins / chemistry
  • Bacterial Proteins / genetics
  • Bacterial Proteins / metabolism
  • Dose-Response Relationship, Drug
  • Drug Evaluation, Preclinical
  • Gene Transfer, Horizontal / drug effects
  • Gonadal Steroid Hormones / chemistry
  • Gonadal Steroid Hormones / metabolism
  • Gonadal Steroid Hormones / pharmacology*
  • Humans
  • Indoles / chemistry
  • Indoles / pharmacology
  • Inhibitory Concentration 50
  • Models, Molecular
  • Plasmids / genetics
  • Protein Conformation
  • Pseudomonas aeruginosa / cytology
  • Pseudomonas aeruginosa / drug effects
  • Quorum Sensing / drug effects*
  • Tyramine / analogs & derivatives
  • Tyramine / pharmacology

Substances

  • Bacterial Proteins
  • Gonadal Steroid Hormones
  • Indoles
  • indoline
  • hordenine
  • Tyramine

Grants and funding

OMV was supported by FRS-FNRS (Belgium). TR is indebted to the AUF (Agence Universitaire de la Francophonie, Madagascar – Belgium) and the CUD (Coopération Universitaire pour le Développement, Belgium). The authors thank CNRS (France) and ANR (project SVSE7 2011 ECORUM) for financial support. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.