How microbial screening is uncovering buried treasure

Genome scientist Craig Venter is cruising the world in his yacht, sampling the genetic diversity of marine bacteria and microbes wafted over the oceans by intercontinental winds, and finding enough genetic treasure to keep drug-hunters in work for a few centuries.

Lacking a luxury yacht, Sydney biopharma Microbial Screening Technologies (MST) is limited to hunting for buried treasure. It is exploring the microbial diversity to the terrestrial biosphere.

Between them, they are confirming the prescience, from a biological perspective, of Hamlet's reflection on the limits of human knowledge: "There are more things in heaven and earth, Horatio, than are dreamt of in your philosophy."

But MST's CEO Ernest Lacey says the company is leaving all that DNA code and its products to protein and peptide experts. The main game for his unlisted company is the immense diversity of small-molecule metabolites arising from all that genetic activity in soil microbes -- bacteria, fungi, protozoans and nematodes.

This week, MST signed a collaborative research agreement with the University of Queensland's Institute for Molecular Bioscience, which the partners believe will significantly accelerate the discovery of new antibiotics, and drugs for a range of important human diseases.

What makes MST different from other bioprospecting companies, Lacey says, is that it now has the means to rapidly screen microbial metabolities for promising drug activity, using a range of unique bioassays developed by IMB experts.

"We're trying to understand both the biology and chemistry that make up soil microbes, before we even begin screening in some else's assays," he says.

"The traditional approach never addressed the fundamental problems involved in dealing with such diversity. It just involved building libraries of compounds, and pushing them against standard cellular bioassays."

In contrast, IMB is developing assays based on distinct classes or sub-types of cellular receptors, or ion channels, that have been linked to specific biological functions or pathways -- for example, the nicotinic acetylcholine receptor, the target of Metabolic Pharmaceuticals' peptide therapy for chronic neuropathic pain, derived from cone shell venom.

IMB researcher Prof Rob Capon says that, from the institute's perspective, it now has access to one of the world's largest ready-made libraries of microbial diversity. MST has accumulated 400,000 isolates of fungi, actinomycetes and other bacteria, to search for new chemistries that could give rise to potent new drugs with novel and highly selective activity.

Capon says that in the past 50 years, more than half of the major breakthroughs in the pharmaceutical industry have been natural products, and around 60 per cent of chemotherapeutics reaching late-stage clinical trials have been of microbial origin.

Focus on new molecules

He says biodiscovery at IMB has leap-frogged the expensive, time consuming process of collecting and cataloguing microbial diversity, allowing researchers to focus immediately on identifying new biologically active molecules.

Lacey says the company will typically run each organism through about 10 of its own screens to profile the biological and pharmacological activity of its metabolites. These metabolities are then screened against new assays for highly specific activity, developed by IMB researchers.

"Rob Capon has developed a new bioassay, which he used to screen 500 extracts from our microbes, and found 10 with promising activity," Lacey says. "We then sift the extracts and pull out the particular molecules responsible for the activity. It's very quick -- with conventional methods, you might spend three or four years working on the molecules, without knowing which of them are interesting.

"It's the way you're most likely to find novel activity, and the diversity of metabolites is so great that it's unlikely anyone else will already have found the same molecule by chance."

And that diversity is literally only scratching the surface, according to Lacey. He says a single cubic centimeter of soil contains a complex ecosystem, and an enormous diversity of microbes. Over billions of years, the struggle to compete and survive has seen each microbe evolve its own arsenal of metabolites with anti-fungal, anti-bacterial, nematicidal or anti-protozoan activity.

"We're a small, innovative company, and IMB is at the leading edge of molecular technology," Lacey says. "One of IMB's major strengths is that their philosophy is not only making discoveries, but making them in a way where they can be helpful tools and resources for further discovery.

"They're helping is get a handle on biodiversity, and were beginning to make discoveries very rapidly -- as soon they develop a new assay, we can put some unique biodiversity against it to see what we can find."

Lacey says the great advantage of small-molecule metabolites over proteins and peptides is that over billions of years, microbes have evolved to use low molecular-weight compounds to handle virtually all of their survival functions -- their approach is minimalist, yet optimised for survival.

The diversity of microbes in soil is phenomenal, and the number of potential interactions between them rises exponentially with species diversity -- and so does the diversity of metabolites.