London: In a cramped lab in rural Pennsylvania, surrounded by technicians in obligatory white lab coats and fume hoods leaking an occasional acrid smell, Neil Pearson holds up a plastic model of a chemical compound that resembles a spidery piece of Lego.
Pearson, a 54-year-old chemist and senior fellow at British pharmaceutical giant GlaxoSmithkline Plc, explains how he spent more than a decade tinkering with chemical compounds before engineering a molecule that may yield the industry’s first truly new antibiotic in 30 years to fight the rise of superbugs that risk killing an extra 10 million people every year by 2050.
Adverse reactions, including possible eye and heart problems discovered in animals, forced Pearson to start over multiple times, with each re-jigging of the compound’s atomic structure requiring a fresh round of tests to prove it was safe and effective. Pearson, wearing clear lab glasses, likens it to a game of snakes and ladders.
“I ain’t got many ladders, but I have tons of snakes,” he says in an accent that gives a hint of his childhood growing up in Dudley, an industrial town in the English Midlands. “I am stubborn. It’s so hard. You get lots of knockbacks.”
Pearson’s slicked back salt-and-pepper hair is just one sign of his years in the lab doing what few pharmaceutical companies are doing these days: trying to come up with novel ways to kill bacteria that have become increasingly resistant to existing antibiotics. In 2007, he uprooted his family from England to work in Glaxo’s research hub, set amid rolling farmland an hour outside Philadelphia.
Glaxo is now testing Pearson’s drug, gepotidacin, on gonorrhea patients in the US after trailing it on patients with severe skin infections. With lab studies suggesting it could fight plague, a potential bioterrorism agent, it’s among only eight genuinely new classes of antibiotics in clinical development anywhere in the world.
Not since Eli Lilly & Co. discovered daptomycin in 1984 has the pharmaceutical industry come up with a completely novel antibiotic, according to the Pew Charitable Trusts. During that time, all but a few big pharma companies have shuttered their bacterial research units, shrinking the universe of expertise.
Just this month, AstraZeneca Plc became the latest big pharmaceutical company to pull out of antibacterial drug development when it sold its antibiotics business to Pfizer Inc. GlaxoSmithKline is one of the few big players that’s kept at it, sinking about $1 billion of its own money over the past decade into antibacterial research.
“It doesn’t feel like we have a sustainable solution for what bugs will throw at us over the next five to 10 years”
Alarming reports keep coming about bacteria that can evade modern medicine’s trusted arsenal of antibiotics. This month, researchers at the University of Cambridge found that a quarter of all supermarket chicken sold in Britain harbours drug-resistant E. coli, which can cause kidney failure and, in severe cases, death. Also this month, the Centers for Disease Control and Prevention reported a fourth US case of a superbug carrying the so-calledmcr-1 gene that makes bacteria resistant to the last-resort antibiotic colistin.
The infections have rattled scientists, coming less than a year after researchers first reported the gene in China, where the antibiotic is used frequently in farm animals. Adding to the worrying reports, the CDC reported that US cases of gonorrhea showing resistance to the recommended treatment regimen had quadrupled from 2013 to 2014.
Fears of superbugs spreading have prompted the United Nations to convene ahigh-level meeting with heads of state in New York Wednesday to devise ways to combat antimicrobial resistance. The meeting comes two years after the World Health Organization warned that, without action, the planet was headed for a post-antibiotic era, in which common infections and minor injuries that have been treatable for decades could once again kill.
“High-tech medicine faces a very substantial threat,” potentially jeopardizing everything from intensive care units to major surgery, says David Livermore, a professor of medical microbiology at the University of East Anglia, north of London. “We face major resistance problems with gonorrhea and tuberculosis.”
Despite the rise of superbugs, big pharma has largely exited antibiotic research because the payoff is so low. Even if Glaxo brings a new medication to the market, by definition it can’t be a blockbuster drug. Overuse of antibiotics has encouraged resistance, which means new treatments must be used sparingly.
Last year, Glaxo sold £712 million ($930 million) of antibacterials, mostly its widely-prescribed penicillin-based Augmentin. These days, antibiotics are largely off patent and cheap. Unlike profitable cancer or heart medications that patients can take for years, antibiotics can save lives but are used for just weeks.
Investors have criticized Glaxo’s departing chief executive officer Andrew Wittyfor overseeing what they perceive as a weak research and development pipeline just as the company’s best-selling asthma drug Advair is bracing for generic competition in the US Witty, 52, who received a knighthood in 2012, will step down in March, leaving antibiotics research bereft of one of its biggest champions. His successor will be Emma Walmsley, London-based Glaxo announced on Tuesday.
“He feels the industry should do something,” says Roy Anderson, 69, professor of infectious disease epidemiology at Imperial College, London and a board member at Glaxo.
Witty’s gamble is beginning to bear fruit. This week, the US Food and Drug Administration gave gepotidacin special status that will speed up its review and extend market exclusivity if it is approved. In addition to gepotidacin, Glaxo has just started testing on people another experimental antibiotic called GSK3342830. It shows promise in fighting germs harbouring the mcr-1 gene as well as the group of so-called gram-negative bacteria whose outer membranes make them better at evading drugs.
While it’s not in a new class of antibiotics and it’s early days, it may address the growing problem of infections picked up in hospitals that don’t respond to the current treatment war chest.
Few companies understand the scientific challenges of developing a new antibiotic better than Glaxo. More than a decade after Alexander Fleming discovered penicillin by accident in 1928 at his London lab, Oxford University scientists Howard Florey and Ernst Chain turned it into a drug that could be mass produced. It was Glaxo that manufactured the majority of Britain’s penicillin used during World War II, saving the lives of thousands of soldiers.
Penicillin changed the world. Infections that previously killed people were now treatable, paving the way for safer operations from organ transplants to hip replacements. Penicillin’s discovery ushered in the golden age of antibiotic research from the 1940s to the 1970s. Many of the drugs in use today are derived from penicillin, which forms the backbone of an antibiotic family known as beta-lactams. They work by blocking the construction of bacterial cell walls.
There have been decades of modifications of that class of antibiotics as bacteria continue to mutate to confer resistance. Of the 37 antibiotics currently in clinical trials, about a quarter involve some form of beta-lactam inhibitors and fewer than 10 are genuinely new-class, according to the Pew Charitable Trusts.
“It doesn’t feel like we have a sustainable solution for what bugs will throw at us over the next five to 10 years,” said David Payne, the head of Glaxo’s antibacterial research. “We’re playing catch-up.”
Payne, a 51-year-old Brit from South London with sandy-brown hair, ought to know. Ever since earning his doctorate at the University of Edinburgh in 1990, he’s watched an explosion of what’s called extended-spectrum beta-lactamases, or ESBLs -- enzymes produced by bacteria to destroy penicillin and its variants. He identified a few on his own while doing his PhD, and then watched the number of ESBLs mushroom from a handful into the hundreds today.
ESBLs infiltrate bacterial communities on the back of plasmids. These mobile loops of DNA act like silicon chips, arming microbes with extra genetic tools to help them survive in hostile environments. Passed from bacteria to bacteria through a form of microbial sex, plasmids enable antibiotic-resistance genes to spread like wildfire.
The recent discovery of the gene causing resistance to colistin, the last-resort antibiotic, is significant because it’s carried on a plasmid. In other words, it’s bound to spread.
In 1995, while working for Smithkline Beecham Plc, which Glaxo bought in 2000, Payne thought the mapping of bacterial genomes would usher in a new age of antibiotic discovery. He set out on an ambitious research program identifying 70 different genes that bacteria needed in order to survive.
Payne’s team then proceeded to screen those 70 targets against a million different chemical compounds to see if any of them would kill bacteria. The process took seven years and the results were disappointing. He found only five compounds that were worth pursuing, but all of them eventually failed. Pfizer and AstraZeneca had also tried the same approach with similar disappointing outcomes, he says.
Not the way
“We learned a lot,” Payne says. “We learned that wasn’t the way to spend a lot of time and money trying to find antibiotics.”
Since then, his team has pursued an exhaustive process of fiddling with chemical structures to find molecules that can disarm bacteria in new ways. Stephen Baker, head of chemistry at Glaxo’s antibacterial research unit, is another Brit transplanted to the middle of rural Pennsylvania trying to crack the antibiotic puzzle. Holding up a multicolored 3-D printed model of an enzyme, he modestly compares his job to his son playing with Lego.
“I realized that’s what we do — we’re Lego engineers, but with no instruction manual,” he says.
Finding a compound that can shut down bacteria is relatively easy, Baker says, but discovering one that won’t kill the patient in the process is much harder. Unlike say antihistamines, where the typical dose is in milligrams — think of tiny hay fever pills — antibiotics are usually prescribed by the grams, making them potentially more toxic.
In 2007, after a decade of tinkering, Pearson finally zeroed in on gepotidacin, one of four molecules that showed potential after Glaxo screened a set of compounds from another, non-antibiotic program. Three of those compounds successfully disabled bacteria in the lab, but failed safety tests in animals.
Once Pearson was satisfied that gepotidacin was safe, he demonstrated that it worked differently to any antibiotic on the market in the way it inhibits gyrase, an enzyme that enables bacterial cells to replicate their DNA as they multiply.
“We believe there is a very good innate barrier to resistance in this medicine,” Witty told investors in New York in November, adding that results show gepotidacin is working against gonorrhea.
Despite all the time, effort and money Glaxo has spent, gepotidacin won’t knock out all superbugs. Though it’s active against staphylococcus bacteria, including the superbug MRSA, and has potential against multi-drug resistant E.coli found in many urinary tract infections, it’s not hitting the broad spectrum of so-called gram-negative pathogens that often cause difficult to treat infections.
“Gepotidacin is nice to have in the arsenal, but it’s not the next penicillin,” says the University of East Anglia’s Livermore. “It’s arguable whether money gets you there or luck gets you there. Those who spent large amounts of money, including Glaxo, haven’t been massively successful.”
Payne agrees that the potential return on Glaxo’s investment isn’t commensurate with the work they did. “It’s taken a really long time and a lot of resource to get to this point,” he says.
It doesn’t square with big pharma’s traditional model of bringing blockbuster drugs to the market that recoup many times their research and development costs in profit.
In Glaxo’s case, it also received help from American taxpayers. The Defense Threat Reduction Agency, part of the US Defense Department, and the Biomedical Advanced Research and Development Authority, part of the Department of Health and Human Services, agreed to provide a total of $240 million to fund the company’s antibiotics research in separate grants.
The cost of bringing an antibiotic candidate to market is about $1 billion and takes an average of a decade, according to Anderson, the Imperial College professor and Glaxo board member. With the need to test drugs in hundreds of patients, sometimes with life-threatening infections, development costs can skyrocket, with no guarantee of success. In fact, only one in five antibiotics entering human testing will be approved by regulators, according to the Pew Charitable Trusts.
Time is running out for patients. Sepsis caused by drug-resistant bacteria is killing more than 56,000 newborns in India and almost 26,000 in Pakistan each year, researchers Ramanan Laxminarayan and Zulfiqar Bhutta wrote in the Lancet Global Health journal this month.
In May, Jim O’Neill, the former Goldman Sachs economist who led a two-year review into antimicrobial resistance for the British government, warned that superbugs will cost the global economy $100 trillion by 2050 if nothing is done.
“It’s all our fault,” Anderson says. “We’re so obsessed with safety that we demand clinical trials that investigate every possible side effect of any chemical intrusion in our body. It’s understandable. But that comes with a cost.” Bloomberg