ACTINOGEN � Uncovering a hidden source of new antibiotics In recent years, the emergence of multiple-drug-resistant bacteria has created a major health threat, for example through hospital-acquired infections from drug-resistant 'superbugs' such as MRSA (Methicillin-resistant Staphylococcus aureus) and the rapidly emerging multi-drug resistant Gram negative hospital infections. It has also allowed the resurgence of 'old' diseases that we thought were things of the past, such as new strains of tuberculosis against which existing drugs are powerless.

It was to meet the unaddressed need for new antibiotics that the ACTINOGEN research project began in 2005, supported by funding provided under the European Union's 6th Research Framework Programme (FP6). The aim was to discover whether genetic techniques could be used to create new antibiotics from bacteria commonly found in garden soil.

Known as streptomycetes, these bacteria were already recognised as a source of antibiotics. But a turning point came in 2002, with the first completion of the sequencing of the genome for one species of the bacterium, Streptomyces coelicolor.

As the ACTINOGEN project coordinator, Professor Paul Dyson of the Institute of Life Science at Swansea University in the UK explains, unravelling the secrets of the genome revealed a new mystery. It was known that the bacterium produced four different antibiotics “ but the genome sequence revealed the potential for around 20. The known antibiotics represented only 20% of the possible total. The genetic coding for production of the other 80% lay in 'cryptic pathways', hitherto lying undetected within the genome.

'We could see the genes were there, but there was no product,' explains Professor Dyson. 'The big question was whether this genetic information was just redundant, or whether it could be used to trigger the production of new antibiotic compounds.'

Meanwhile, the genomes of other streptomycete species had been sequenced and all had shown the same pattern, with between 12 and 15 'cryptic pathways'. 'If you wanted to discover new antibiotics, this had enormous implications,' says Professor Dyson.

During the project, ACTINOGEN scientists successfully triggered the creation of new antibiotics using the cryptic pathways of a number of streptomycete species, thus confirming that here indeed was a rich seam of potential new drug discovery. With thousands of streptomycete species already known to science, and many more still undiscovered in nature, the potential to generate huge numbers of new antibiotics was clear.

An equally important part of the project concerned the genetic engineering of a species of streptomycete which could be used as a kind of 'all-purpose' production facility, able to synthesise the new antibiotics in sufficient quantity. Known as a 'generic Superhost', it allows the genetic coding for any desired antibiotic to be taken from its original bacterial host, where the production process may be difficult and slow, and implanted in the Superhost, which then produces the antibiotic in much greater quantity than is otherwise possible.

In the past, says Professor Dyson, achieving the necessary level of production took around 10 years. The ACTINOGEN Superhost allows the same result to be achieved within six months to one year.

The ACTINOGEN results, which have already led to the filing of six patents, clearly offer the prospect of a revolution in antibiotic production “ opening up the possibility of a range of potential new drugs, with important benefits not only for human health, but also for public health budgets and for the European biotechnology industry.