The fight against antibiotic-resistant superbugs has taken a step
forward thanks to a new discovery by scientists at The University of
A multi-disciplinary research team at the University’s Centre for
Biomolecular Sciences has uncovered a new way of inhibiting the toxicity
and virulence of the notorious superbug, Pseudomonas aeruginosa.
This bacteria produces an armoury of virulence factors and is
resistant to many conventional antibiotics. It is almost impossible to
eradicate P. aeruginosa from the lungs of people with cystic
fibrosis and is therefore a leading cause of death among sufferers. The
bug also causes a wide range of infections particularly among hospital
The new discovery concerns the bacterial cells’ ability to ‘talk’ to
each other by producing and sensing small chemical signal molecules.
This is called ‘quorum sensing’ (QS) and enables a population of
individual bacteria to act socially rather than as individuals. QS
allows a population of bacteria to assess their numerical strength and
make a decision only when the population is ‘quorate’.
The mechanism through which QS signals work is by activating gene
expression upon interaction of a QS signal molecule with a receptor
protein. In many disease-causing bacteria, QS controls genes which are
essential for infection. These genes code for virulence factors such as
toxins which cause damage to host tissues and the immune system.
Interfering with the QS signalling process blocks bacterial virulence
and renders bacteria unable to cause infection. Consequently QS systems
are molecular targets for the development of new anti-infective drugs
which do not kill bacteria but instead block their ability to cause
In a study published in the journal, PLOS Pathogens, the Nottingham team has described how they solved the 3D structure of a receptor protein called PqsR used by P. aeruginosa
to sense alkyl quinolone QS signal molecules so that they could
visualize the shape of the QS signal molecule-binding site within the
Professor of Molecular Microbiology, Paul Williams, said: “We were able to synthesize and screen a library of chemical compounds which could fit within the PqsR binding site and block receptor activation by the QS signal molecules. The active compounds were screened for their ability to inhibit QS and through a process of chemical refinement some novel potent QS inhibitors were discovered which were tested biologically on P.aeruginosa and shown to block virulence gene expression.”
Professor of Macromolecular Crystallography, Jonas Emsley, added:
“This ground-breaking work establishes a platform for the future
evaluation and further development of these new QS inhibitor compounds
as potential drugs for the treatment of P. aeruginosa infections.”
The research was funded by the Biotechnology and Biological Sciences Research Council (BBSRC).
Full bibliographic informationStructural Basis for Native Agonist and Synthetic Inhibitor Recognition by the Pseudomonas aeruginosa Quorum Sensing Regulator PqsR (MvfR)
Aravindan Ilangovan, Matthew Fletcher, Giordano Rampioni, Christian Pustelny, Kendra Rumbaugh, Stephan Heeb, Miguel Cámara, Alex Truman, Siri Ram Chhabra, Jonas Emsley, Paul Williams.
PLoS Pathog 9(7): e1003508. doi:10.1371/journal.ppat.1003508
Source: The University of Nottingham via AlphaGalileo