Oxford researchers find possible new type of antibiotic

Apr 26 2004

Dr Ben Davis in the Department of Chemistry at Oxford University, England and his collaborators have discovered a possible new route to antibiotics.

A novel carbohydrate and protein conjugate, known as a 'glycodendriprotein', may stop bacteria earlier in the infection process than most antibiotics do, with the additional advantage of not becoming obsolete as bacteria evolve.

Dr Davis and his colleagues have shown that by linking branched carbohydrate-tipped structures called glycodendrimers to a protein-degrading enzyme, they can inhibit the infectivity of a certain bacterium (Actinomyces naeslundii).

Each glycodendrimer consists of a number of sugar molecules on the end of a scaffold-like structure. By changing the 'scaffolding' to give more or fewer 'arms' for the sugar tips, the scientists can affect what the glycodendrimer will bind to. By then attaching enzymes to the glycodendrimer that will eat away at bacteria, they can create a sort of 'search and destroy' vehicle: the carbohydrate-tipped structures bind to the right bacterium, and then the protein eats away at the bacterium's surface, stopping it in its tracks.

When bacteria invade your body, they attach themselves to your cells and envelop them. The glycodendriproteins stop them in two ways: firstly, by binding to a bacterium, they inhibit its ability to bind to the host cells that it wants to infect. Next, the enzyme chews up the bacterium's outer layer proteins, stopping it from being able to bind permanently.

'We're trying to block infection before it even gets going,' said Dr Davis. 'The glycodendrimer inhibits the binding, but then the enzyme that is attached to the glycodendrimer swings around, chews up the protein on the surface, and renders it unable to grab hold of the host it wants to infect.'

Carolyn R Bertozzi, a professor of chemistry at the University of California, Berkeley, who also studies glycoconjugates, said that the new approach would avoid the problems which occur when bacteria become resistant to drugs through rapid adaptive mutation – the process which is believed to have led to the 'superbugs' seen in hospitals.

'While bacterial proteins can become resistant to drugs via rapid mutation, the actual carbohydrate-binding residues in these bacterial adhesins are under pressure to remain conserved, as they are vital for the colonizing activity of the bacterial cell,' she said. 'Thus, any approach that targets the carbohydrate-binding activity is less likely to suffer from the selection of resistant strains. Although its reduction to clinical practice is a way off, as a concept I think this is an interesting combination of antiadhesive therapy and receptor-mediated drug delivery that will prompt new ways of thinking about antibiotic design.'

Dr Davis's collaborators include Marjorie M Cowan of Miami University in Ohio, Professor Bryan James of Toronto University, and Dr Rick Bott of Genencor International, Palo Alto.