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 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 favor 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.
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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 defense
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 centers, 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 center 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)
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