BioEd Online

Scientists have overcome an important hurdle in the race to develop new antibiotics: they have made bacteria efficiently churn out chemicals that could prove to be useful drugs.

Over the past few decades, bacteria have evolved to resist our antibiotics. As a result, hospitals have seen a dramatic rise in drug-resistant infections, many of which are fatal.

To come up with new antibiotics, scientists often work with the natural chemical defences of fungi and bacteria, altering these natural antibiotics to make new ones.

Researchers have also attempted to genetically engineer bacteria to pump out new chemicals directly. Although chemicals produced this way have not yet been used to fight human disease, the approach has produced some promising compounds, including those in a class called lantibiotics.

But scientists have stumbled in trying to get bacteria to spit out chemicals belonging to a class known as polyketides. Polyketides are molecules that contain large rings of carbon and oxygen atoms, and include the well-known antibiotic erythromycin.

Now Daniel Santi of the Hayward, California-based company Kosan Biosciences and his colleagues have cracked the problem.

The advance is welcome in a field running dry of ways to make new antibiotics, says pharmacologist Jon Clardy of the Harvard Medical School in Boston. "The need is obvious, and there has been very little in the way of new antibiotics in the past decade," he says.

Mix and match

Santi's team took DNA sequences that produce bits of the proteins that make polyketides from several different bacteria, and mixed and matched them inside Escherichia coli bacteria.

This much has been done before. But the hard part was getting the resulting bits of protein to combine into a functioning polyketide-making machine. Polyketide proteins are very large, so it is particularly difficult to get the components to attach together.

To achieve this, Santi's team added special sequences to the ends of their genetic fragments that in turn made the protein fragments 'sticky'. This meant the protein bits joined up "like Lego building blocks", resulting in new proteins conformations and new polyketides, they report in Nature Biotechnology¹.

The team has yet to test whether these polyketides have antibiotic powers. But they anticipate that at least some will be useful.

Santi adds that a few natural polyketides attack cancer cells, so some of the bioengineered ones might have anti-cancer properties too.