Extreme medicine — the search for new antibiotics

NORWICH, England — Pampering leafcutter ants with fragrant rose petals and fresh oranges may seem an unlikely way to rescue modern medicine, but scientists at a lab in eastern England think it’s well worth trying.

As the world cries out for new antibiotics, researchers at the John Innes Centre (JIC) in Norwich are also taking a bet on bacteria extracted from the stomachs of giant stick insects and cinnabar caterpillars with a taste for highly toxic plants.

Their work is part of a new way of thinking in the search for superbug-killing drugs — turning back to nature in the hope that places as extreme as insects’ insides, the depths of the oceans, or the driest of deserts may throw up chemical novelties and lead to new drugs.

“Natural products fell out of favour in the pharmaceutical sphere, but now is the time to look again,” says Mervyn Bibb, a professor of molecular microbiology at JIC who collaborates with many other geneticists and chemists. “We need to think ecologically, which traditionally people haven’t been doing.”

The quest is urgent. Africa provides a glimpse of what the world looks like when the drugs we rely on to fight disease and prevent infections after operations stop working.

In South Africa, patients with tuberculosis that has developed resistance to all known antibiotics are already simply sent home to die, while West Africa’s Ebola outbreak shows what can happen when there are no medicines to fight a deadly infection — in this case due to a virus rather than bacteria.

Scant financial rewards and lack of progress with conventional drug discovery have prompted many Big Pharma companies to abandon the search for new bacteria-fighting medicines. Yet for academic microbiologists these are exciting times in antibiotic research — thanks to a push into extreme environments and advances in genomics.

“It’s a good time to be researching antibiotics because there are a lot of new avenues to explore,” said Christophe Corre, a Royal Society research fellow in the department of chemistry at the University of Warwick.

Extreme locations, smart techniques

Marcel Jaspars, a professor of organic chemistry at Britain’s University of Aberdeen, is leading a dive deep into the unknown to search for bacteria that have, quite literally, never before seen the light of day.

With 9.5 million euros ($12.7 million) of European Union funding, Jaspars launched a project called PharmaSea in which he and a team of international researchers will haul samples of mud and sediment from deep sea trenches in the Pacific Ocean, the Arctic waters around Norway, and then the Antarctic.

Like the guts of stick insects or the protective coats of leafcutter ants, such hard-to-reach places house endemic populations of microbes that have developed unique ways to deal with the stresses of life, including attacks from rival bugs.

“Essentially, we’re looking for isolated populations of organisms. They will have evolved differently and therefore hopefully produce new chemistry,” Jaspars explains.

Nature has historically served humankind well when it comes to new medicines. Even Hippocrates, known as the father of Western medicine, left historical records describing the use of powder made from willow bark to help relieve pain and fever.

Those same plant extracts were later developed to make aspirin — a wonder drug that has since been found also to prevent blood clots and protect against cancer.

Pfizer’s Rapamune, used to prevent rejection in organ transplantation, came from a micro-organism isolated from soil collected in Easter Island in the Pacific Ocean, and penicillin, the first ever antibiotic, comes from a fungus.

Cubicin, an injectable antibiotic sold by US-based Cubist, was first isolated from a microbe found in soil collected on Mount Ararat in eastern Turkey.

In all, more than half of all medicines used today were inspired by or derived from bacteria, animals or plants.

Yet as Jaspars says: “It’s not just about going to extreme locations, it’s now also about using smart techniques.”

Modern gene-sequencing machines mean it is now possible to read microbial DNA quickly and cheaply, opening up a new era of “genome mining”, which has reignited interest in seeking drug leads in the natural world.

It marks a significant change. In recent decades drug developers have focused on screening vast libraries of synthetic chemical compounds in the hope of finding ones capable of killing bad bugs. Such synthetic analogues are easier to make and control than chemicals from the wild, but they have yielded few effective new drugs.

The problem is they just don’t have the natural diversity of compounds that have evolved over billions of years as defence mechanisms for wild bacteria and fungi.

“We need new scaffolds, new structures and that is what natural products bring,” Corre says.

Five million trillion trillion bacteria

In the chase for new compounds generated by microbes to fight off their foes, scientists have no shortage of targets. Humans share the Earth with an awful lot of bacteria — around 5 million trillion trillion of them, according to an estimate in 1998 by scientists at the University of Georgia. That’s a 5 followed by 30 zeroes.

And as well as hunting in extreme places, there is a lot more scientists can do to explore the potential of better-known bacteria, such as species of Streptomyces found in the soil, long a rich source of antibiotics. Streptomycin, a commonly used antibiotic, was the first cure for tuberculosis and saved many lives from being lost to the lung disease until the bacteria that causes it began to develop resistance.

After publication of the first genome for a strain of Streptomyces bacteria in 2002, researchers can see that much of the antibiotic potential of this vast family of organisms remains untapped.

The DNA analysis showed that up to 30 different compounds could be extracted from just this one strain of Streptomyces — many of them ones that haven’t yet been examined for their bug-killing capacity.

Understanding the genetic coding also opens up the possibility of developing ways of turning microbial genes on or off to generate production of a specific antibiotic.

This can involve removing repressors that silence gene expression or adding activators to turn them on. Scientists are also using synthetic biology to insert genetic sequences into easily managed host cells to produce a certain compound.

The field is exploding. China’s BGI, for example, one of the world’s biggest genomics centres, is sequencing thousands of different bacteria, and similar work at other labs is adding to a mountain of data for scientists to work through.

It also provides insights into how antibiotic resistance occurs, with researchers at Britain’s Wellcome Trust Sanger Institute this month reporting a new way to identify such gene changes, potentially paving the way to more targeted treatments.

These advances are tempting some large drugmakers back to the antibiotic space, with Swiss-based Roche now looking to apply its skills in genetics and diagnostics in antibacterial research.

France’s Sanofi, too, is also paying more attention by striking a deal with German research centre Fraunhofer-Gesellschaft to scour the natural world for new antibiotics, while Britain’s GlaxoSmithKline says it remains committed to the field.

Yet the overall industry effort is paltry when compared with the billions of dollars spent on other disease areas, leaving scientists worried as to whether their promising ideas will find a commercial sponsor to bring them to market.

It is a commercial gap that alarms policy makers, too.

“Antimicrobial resistance is not a future threat looming on the horizon. It is here, right now, and the consequences are devastating,” Margaret Chan, Director General of the World Health Organisation, told a ministerial conference on antibiotic resistance in June.