* World crying out for new antibiotics as superbugs evolve
* Scientists seek new chemistry in hard-to-reach places
* "Back to nature" search aided by genome mining technology
By Kate Kelland and Ben Hirschler
NORWICH, England, Aug 17 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 U.S.-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
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
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
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 policymakers, 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 Organization, told a ministerial conference on antibiotic
resistance in June.
($1 = 0.7469 Euros)
(Editing by Will Waterman)