Fight against superbugs goes underground

Scientists are pioneering a way of discovering new antibiotics by analysing the entire genetic blueprint of soil microbes which kill their competitors by producing natural toxins. Screening soil microbes for novel antibiotics is a traditional method of discovering new drugs but the rise of resistant strains of "superbugs" is forcing scientists to take a far more radical approach to drug discovery.

One method involves analysing the genes of soil microbes by a process known as "genome mining" – analysing the entire DNA of the micro-organism – to identify new classes of antibiotics that the microbe may have been capable of making before.

"Most clinically useful antibiotics come from soil micro-organisms, soil bacteria and soil fungi, and they make those compounds, we believe, to compete in their natural environment against other soil microbes," said Professor Mervyn Bibb of the John Innes Centre in Norwich.

"Genome mining [involves] the sequencing of these microbes and from this it is apparent that they have the potential to make many more antibiotics than we previously thought. We are devising different genetic tricks to activate or awaken these different cryptic gene clusters to make novel compounds. It's still at an early stage but if we could multiply the number of known antibiotics ten fold then we'd be in much better situation than we are in today."

Once the genes have been found the antibiotics can be synthesised in the lab. It is hoped that by developing new ways of "mining" microbes in the soil in the search for novel antibiotics it will be possible to combat the rising tide of drug-resistant bacteria threatening to overwhelm the health advances of the past half-century.

Since antibiotics were first used during the Second World War they have saved countless lives but a growing number of infectious diseases – from TB to hospital-acquired infections – are becoming resistant to all but a few drugs, and some "superbugs" are resistant to all antibiotics.

Professor Tony Maxwell, head of biological chemistrty at the John Innes Centre, said there was an urgent need to come up with new ways of developing antibiotics because fewer and fewer of the drugs were coming on to the market each year.

"It's largely because they are no longer a really profitable exercise for the big pharma companies and so academic labs like ours have to step in and contribute to the drug-discovery process," Professor Maxwell said. "What we are trying to do is to develop new agents that will be the drugs of the future that will help to combat drug-resistant bacteria."

Another way of discovering new chemicals with antibiotic effects is to analyse the genetic and metabolic makeup of disease-causing bacteria to identify weak points that scientists can "target" with tailor-made drugs.

Scientists at the John Innes Centre have found one such drug target in the bacterium that causes tuberculosis, which infects a third of the world's population and suffers a growing problem with drug-resistant strains.

"It's fascinating in that this target actually tricks the bacteria into suicidal self poisoning and the data we have so far suggests that this target is as good as the current front-line drug," said Steph Bornemann, of the John Innes Centre.

One example where a new antibiotic is needed is for TB, which scientists once believed could be eradicated. But it has since re-emerged as a major global health threat and some strains are resistant to present drugs.

The scientists hope that they will be able to develop an antibiotic that can cause TB microbes to commit suicide. "It's very much at the first stage of the drug-development pipeline, and that timescale is quite long," Dr Bornemann said. "We talking many years and a significant amount of investment,"