1. Extreme medicine: The search for new antibiotics
By Kate Kelland and Ben Hirschler
NORWICH England Sun Aug 17, 2014 4:16am EDT
1 of 2. Streptomyces coelicolor is seen in this undated handout photograph released in London
August 8, 2014.
Credit: Reuters/Mervyn Bibb and Andrew Davis/John Innes Centre/Handout via Reuters
NORWICH England (Reuters) - 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 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
2. 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 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
3. Â Â Â 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 http://ge.tt/8x5zhrq1/v/0 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.
4. ($1 = 0.7469 Euros)
(Editing by Will Waterman)
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