Imperial reveals a potential route to new antibiotics

In the quest to devise molecules that tamper with bacteria, the pharmaceutical industry is some way off the pace set by nature's experts. Some specialised viruses have been running their own drug screening programme for millions of years.

Many of these viruses employ elegant strategies to sabotage their bacterial hosts in order to exist and reproduce. So for scientists aiming to design better antibiotics, it's natural that viruses that infect bacteria should provide inspiration. Researchers at Imperial College London have published the first detailed description of how a small molecule produced by a virus enables it to hijack bacteria's cellular equipment. The findings, published in Molecular Cell, provide a platform for the development of new drugs to fight infections.

An important target in bacteria for manipulation by these specialised viruses, called phages, is RNA polymerase. This essential enzyme enables the instructions encoded in the bacteria's genes to be read and turned into proteins. A phage, called T7, infects the bacteria Escherichia coli and produces a small protein that subverts the normal workings of RNA polymerase in order to facilitate its own replication. Now Dr Sivaramesh Wigneshweraraj from the Department of Medicine and Professor Steve Matthews from the Department of Life Sciences have discovered how this protein, called Gp2, interacts with the bacterial enzyme to stop it from functioning.

The findings, which build on their previous work revealing the structure of Gp2 bound to its target on the RNA polymerase, could provide inspiration for new strategies to attack bacteria. The enzyme is already targeted by an existing antibiotic, rifampicin, which is commonly used to treat tuberculosis and MRSA, but bacteria can develop resistance to the drug relatively easily.

"Gp2 binds to a different part of RNA polymerase from rifampicin, and it binds much more tightly," Dr Wigneshweraraj said. "This tells us where to find the enzyme's Achilles' heel, and gives us a platform to develop drugs that exploit this weak spot. Antibiotic resistance is becoming a bigger and bigger problem all the time, so clues that point towards new drugs that work differently to existing drugs are extremely valuable."

RNA polymerase is often described as having a shape like a crab claw. The pincers come together to form a channel where DNA can bind. One mode of action for the protein Gp2 is to inhibit the binding of DNA.

RNA polymerase isn't shut down completely by the viral protein. It can still make the proteins the virus wants, but not essential proteins the bacteria need to make in order to grow. This is because RNA polymerase needs an extra component called a sigma factor in order to work. There are seven sigma factors in E. coli's genome, and each one is responsible for enabling a different set of genes to be read. Gp2 specifically inhibits the RNA polymerase with the sigma factor responsible for reading 'housekeeping genes'.

The study was funded by the Biotechnology and Biological Sciences Research Council (BBSRC) and the Wellcome Trust, and the study was conducted in collaboration with Professor Konstantin Severinov and colleagues at Rutgers University in the USA.

Last month saw the opening of the world's first research centre focussing on disease-causing bacteria at Imperial. The MRC Centre for Molecular Bacteriology and Infection (CMBI) spans the Departments of Life Sciences and Medicine, promising to germinate more collaborations of this nature between microbiologists and structural biologists.