Toxin untangled: X-ray clues to pneumonia

Skip to Navigation

Ezine

  • Published: Dec 1, 2015
  • Author: David Bradley
  • Channels: X-ray Spectrometry
thumbnail image: Toxin untangled: X-ray clues to pneumonia

Streptococcus pneumoniae

The Crystal Structure of Pneumolysin at 2.0 Å Resolution Reveals the Molecular Packing of the Pre-pore Complex Marshall et al, Sci Rep

X-ray crystallography at the Diamond Light Source in Oxfordshire, UK, has revealed the structure of the toxin pneumolysin, which is associated with the potentially lethal diseases of bacterial pneumonia, meningitis and septicaemia caused by Streptococcus pneumoniae. The discovery marks the culmination of twenty years of scientific effort and could open up new avenues to treatments for these diseases.

The World Health Organization (WHO) estimates that more than 1.6 million people die every year of pneumococcal infections, more than 800 000 are children under the age of five years. In work funded by the Wellcome Trust and the Medical Research Council (MRC), a team from the University of Leicester used the synchrotron facilities at Diamond to obtain the structure. The three-year study carried out by four teams of collaborators across the University shows how a therapeutic agent might be designed to block assembly of the pneumolysin pore structures that form on the surface of host cells and kill them. As such, the university has established a commercial enterprise, Axendos Therapeutics, to develop such agents and bring them to market.

Collaborative effort

The work was led by Russell Wallis of the Departments of Infection, Immunity and Inflammation and Molecular and Cell Biology and Peter Andrew, Head of Department of Infection, Immunity and Inflammation and the team describes its results in detail in the journal Scientific Reports and explains how the various components of the toxin assemble to form the lethal pores.

"Pneumococcal infections are the leading cause of bacterial pneumonia as well as the cause of a range of other life-threatening diseases," explains Wallis. "Pneumolysin is instrumental in the ability of pneumococcus to cause disease. The aim of the research was to find out how pneumolysin kills our cells, thereby causing tissue damage and contributing to disease. In particular we wanted to find out how multiple copies of the toxin assemble on the surface of cells."

This is the first detailed structure of pneumolysin and also reveals how when the researchers disrupt the assembly contacts that can deactivate the toxin making it non-lethal. "The mode of action of pneumolysin action revealed by our work appears to be conserved in related toxins from other disease-causing bacteria, for example, toxins produced by pathogenic species of Listeria," Wallis adds.

Beating resistance

Andrew points out that, "Because of fears of antibiotic resistance, researchers have been trying for decades to find new antimicrobial drugs but with little success. A new approach is to identify new targets for therapy and our work over a long period shows that pneumolysin is an excellent target for new treatments." The point being that blocking the activity of the toxin released by the bacteria is one step removed from trying to kill the living microbes with antibiotics.

"In the future, we would like to use small molecule screening, e.g. the new fragment screening facility at Diamond Light Source, to identify compounds that bind to pneumolysin and prevent pore formation," Wallis told SpectroscopyNOW. "Although antibiotics can be used to treat pneumococcal disease, they are often associated with significant tissue and organ damage caused by the pneumolysin that is released from the bacteria. The ultimate goal would be to develop a drug that could be used to prevent the harmful effects of pneumolysin, as a standalone therapeutic or in conjunction with antimicrobials/antibiotics."

Related Links

Sci Rep 2015, 5, 13293: "The Crystal Structure of Pneumolysin at 2.0 Å Resolution Reveals the Molecular Packing of the Pre-pore Complex"

Article by David Bradley

The views represented in this article are solely those of the author and do not necessarily represent those of John Wiley and Sons, Ltd.

Follow us on Twitter!

Social Links

Share This Links

Bookmark and Share

Microsites

Suppliers Selection
Societies Selection

Banner Ad

Click here to see
all job opportunities

Most Viewed

Copyright Information

Interested in separation science? Visit our sister site separationsNOW.com

Copyright © 2017 John Wiley & Sons, Inc. All Rights Reserved