Medical Device Daily Contributing Writer

LONDON – An image of the active site of an enzyme that is vital to the survival of the bacterium Staphylococcus aureus could help researchers to identify new antibiotics to treat serious infections.

Because a similar enzyme is present in many other pathogenic bacteria, any new drugs might also be effective against a range of other infections.

Scientists at Imperial College London (ICL), where the image was produced, are already working with the university's Drug Discovery Centre, to trawl for molecules that can fit into the enzyme's active site and prevent it working.

New antibiotics to treat S. aureus infections are urgently needed. This bacterium causes serious infections, which can be life-threatening. Many strains are already resistant to the most commonly used antibiotics, including methicillin; these are known as methicillin-resistant S. aureus or MRSA.

Paul Freemont, professor of protein crystallography, told Medical Device Daily's sister publication, BioWorld International: "The hope is that we will be able to design small molecules that will inhibit the function of this enzyme, which plays an essential role in the growth of the bacterium, and so kill the bacteria."

Freemont, together with his co-author Angelika Grundling, of the department of microbiology at ICL, and their colleagues, have reported their findings in a paper in the Jan. 19 issue of the Proceedings of the National Academy of Sciences. Its title is: "Structure-based mechanism of lipoteichoic acid synthesis by Staphylococcus aureus LtaS".

Grundling, then working at the University of Chicago, was the first to identify the protein, which is called LtaS, as an enzyme responsible for the synthesis of the bacterial cell wall component called lipoteichoic acid (LTA). She also showed that LtaS was essential for the viability of S. aureus under normal growth conditions.

After Grundling moved to ICL, she, Freemont, and their colleagues embarked on solving the structure of LtaS, in a project funded by the Medical Research Council.

Freemont said: "We thought if we had the structure, this would help us to understand what this enzyme actually does, and it would also then provide us with the opportunity to begin an in silico drug discovery program to find molecules that would inhibit it."

Using X-ray crystallography, the team achieved this aim, producing a high-resolution image of the molecule that shows where all its atoms are. The image includes a map of the active binding site.

The PNAS paper describes how most of the enzyme sits on the extracellular surface of the bacterium. The proposed active site lies near the surface, forming a pocket within a relatively flat part of the molecule.

Grundling said: "We know that this surface structure, called LTA, is involved in cell growth and cell division – we have shown that without it the cell cannot grow properly, and eventually dies. Because LtaS is the 'machine' which builds LTA, developing a drug that knocks out the machine will provide us with a new way to disable the growth of these cells, which would represent a novel new treatment for MRSA and other S. aureus infections."

Working with the Drug Discovery Centre at ICL, the project team is now concentrating on finding inhibitors of LtaS.

Freemont said: "We are excited about this finding because LtaS is an extracellular molecule and that means it can be available to drugs. Obviously there is a lot of work to do before we can prove that it is a validated target, but we have already started developing compounds and exploring how these bind to the protein, using the crystal structure that we have. Once we get some initial 'hits' we will test them, using minimum inhibitory concentration assays with the bacteria, to prove that this is a good target."

The researchers are also planning to explore further the biology and function of LtaS. Freemont added: "Interestingly, there are homologues of LtaS in other pathogenic bacteria, and we plan to investigate some of these molecules to see if they can shed more light on the function of the enzyme."