* 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 (Reuters) - Pampering leafcutterants with fragrant rose petals and fresh oranges may seem anunlikely way to rescue modern medicine, but scientists at a labin eastern England think it's well worth trying.
As the world cries out for new antibiotics, researchers atthe John Innes Centre (JIC) in Norwich are also taking a bet onbacteria extracted from the stomachs of giant stick insects andcinnabar caterpillars with a taste for highly toxic plants.
Their work is part of a new way of thinking in the searchfor superbug-killing drugs - turning back to nature in the hopethat places as extreme as insects' insides, the depths of theoceans, or the driest of deserts may throw up chemical noveltiesand lead to new drugs.
"Natural products fell out of favour in the pharmaceuticalsphere, but now is the time to look again," says Mervyn Bibb, aprofessor of molecular microbiology at JIC who collaborates withmany other geneticists and chemists. "We need to thinkecologically, which traditionally people haven't been doing."
The quest is urgent. Africa provides a glimpse of what theworld looks like when the drugs we rely on to fight disease andprevent infections after operations stop working.
In South Africa, patients with tuberculosis that hasdeveloped resistance to all known antibiotics are already simplysent home to die, while West Africa's Ebola outbreak shows whatcan happen when there are no medicines to fight a deadlyinfection - in this case due to a virus rather than bacteria.
Scant financial rewards and lack of progress withconventional drug discovery have prompted many Big Pharmacompanies to abandon the search for new bacteria-fightingmedicines. Yet for academic microbiologists these are excitingtimes in antibiotic research - thanks to a push into extremeenvironments and advances in genomics.
"It's a good time to be researching antibiotics becausethere are a lot of new avenues to explore," said ChristopheCorre, a Royal Society research fellow in the department ofchemistry at the University of Warwick.
EXTREME LOCATIONS, SMART TECHNIQUES
Marcel Jaspars, a professor of organic chemistry atBritain's University of Aberdeen, is leading a dive deep intothe 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 Unionfunding, Jaspars launched a project called PharmaSea in which heand a team of international researchers will haul samples of mudand sediment from deep sea trenches in the Pacific Ocean, theArctic waters around Norway, and then the Antarctic.
Like the guts of stick insects or the protective coats ofleafcutter ants, such hard-to-reach places house endemicpopulations of microbes that have developed unique ways to dealwith the stresses of life, including attacks from rival bugs.
"Essentially, we're looking for isolated populations oforganisms. They will have evolved differently and thereforehopefully produce new chemistry," Jaspars explains.
Nature has historically served humankind well when it comesto new medicines. Even Hippocrates, known as the father ofWestern medicine, left historical records describing the use ofpowder made from willow bark to help relieve pain and fever.
Those same plant extracts were later developed to makeaspirin - a wonder drug that has since been found also toprevent blood clots and protect against cancer.
Pfizer's Rapamune, used to prevent rejection inorgan transplantation, came from a micro-organism isolated fromsoil collected in Easter Island in the Pacific Ocean, andpenicillin, 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 soilcollected on Mount Ararat in eastern Turkey.
In all, more than half of all medicines used today wereinspired by or derived from bacteria, animals or plants.
Yet as Jaspars says: "It's not just about going to extremelocations, it's now also about using smart techniques."
Modern gene-sequencing machines mean it is now possible toread microbial DNA quickly and cheaply, opening up a new era of"genome mining", which has reignited interest in seeking drugleads in the natural world.
It marks a significant change. In recent decades drugdevelopers have focused on screening vast libraries of syntheticchemical compounds in the hope of finding ones capable ofkilling bad bugs. Such synthetic analogues are easier to makeand control than chemicals from the wild, but they have yieldedfew effective new drugs.
The problem is they just don't have the natural diversity ofcompounds that have evolved over billions of years as defencemechanisms for wild bacteria and fungi.
"We need new scaffolds, new structures and that is whatnatural products bring," Corre says.
FIVE MILLION TRILLION TRILLION BACTERIA
In the chase for new compounds generated by microbes tofight off their foes, scientists have no shortage of targets.Humans share the Earth with an awful lot of bacteria - around 5million trillion trillion of them, according to an estimate in1998 by scientists at the University of Georgia. That's a 5followed by 30 zeroes.
And as well as hunting in extreme places, there is a lotmore scientists can do to explore the potential of better-knownbacteria, such as species of Streptomyces found in the soil,long a rich source of antibiotics. Streptomycin, a commonly usedantibiotic, was the first cure for tuberculosis and saved manylives from being lost to the lung disease until the bacteriathat causes it began to develop resistance.
After publication of the first genome for a strain ofStreptomyces bacteria in 2002, researchers can see that much ofthe antibiotic potential of this vast family of organismsremains untapped.
The DNA analysis showed that up to 30 different compoundscould be extracted from just this one strain of Streptomyces -many of them ones that haven't yet been examined for theirbug-killing capacity.
Understanding the genetic coding also opens up thepossibility of developing ways of turning microbial genes on oroff to generate production of a specific antibiotic.
This can involve removing repressors that silence geneexpression or adding activators to turn them on. Scientists arealso using synthetic biology to insert genetic sequences intoeasily managed host cells to produce a certain compound.
The field is exploding. China's BGI, for example, one of theworld's biggest genomics centres, is sequencing thousands ofdifferent bacteria, and similar work at other labs is adding toa mountain of data for scientists to work through.
It also provides insights into how antibiotic resistanceoccurs, with researchers at Britain's Wellcome Trust SangerInstitute this month reporting a new way to identify such genechanges, potentially paving the way to more targeted treatments.
These advances are tempting some large drugmakers back tothe antibiotic space, with Swiss-based Roche nowlooking to apply its skills in genetics and diagnostics inantibacterial research.
France's Sanofi, too, is also paying moreattention by striking a deal with German research centreFraunhofer-Gesellschaft to scour the natural world for newantibiotics, while Britain's GlaxoSmithKline says itremains committed to the field.
Yet the overall industry effort is paltry when compared withthe billions of dollars spent on other disease areas, leavingscientists worried as to whether their promising ideas will finda commercial sponsor to bring them to market.
It is a commercial gap that alarms policymakers, too.
"Antimicrobial resistance is not a future threat looming onthe horizon. It is here, right now, and the consequences aredevastating," Margaret Chan, Director-General of the WorldHealth Organization, told a ministerial conference on antibioticresistance in June. ($1 = 0.7469 Euros) (Editing by Will Waterman)
Glaxosmithkline (GSK)
