In a remote cave 1,600 feet below New Mexico’s Carlsbad Caverns National Park, Hazel Barton, a microbiologist working with Cubist Pharmaceuticals Inc., has found a drug-resistant bacteria that may one day help extend the life of Cubist’s best-selling antibiotic, Cubicin.
“We know what the resistance is going to look like,” said Barton, an associate professor at the University of Akron in Ohio. “There’s no resistance now, but in something like 20 years when there is, we’re going to know how to inhibit it.”
Barton’s discovery in Lechuguilla Cave, where humans have rarely set foot since its opening in 1986, is part of a global hunt for never-before-used antibiotics to combat the spread of drug-resistant superbugs. Last month, the World Economic Forum declared drug-resistant bacteria one of the greatest risks to human health in its 2013 Global Risks report. With the pace of new antibiotic development slowing to a crawl, the report warned that the world may face “a scenario in which all antibiotics are rendered ineffective for treating even common infections.”
As bacteria develop resistance to available medicines, modern methods of antibiotic development in labs have failed to keep pace with an emerging crop of superbugs. Many drugmakers have dropped out of the market because of regulatory hurdles and poor return on investment.
That failure carries a steep price. Antibiotic-resistant infections are estimated to add $21 billion to $34 billion in costs to the U.S. health-care system each year, according to the World Economic Forum’s report. Antibiotic-resistant bacteria cause the majority of the 99,000 deaths annually in North America from infections acquired in hospitals, the report said.
By teaming with Barton, Cubist is betting that drug discovery in nature, long abandoned by many other drugmakers, may hold a key to building its share of the global market for branded antibiotics, estimated at $9.5 billion in 2011, according to data compiled by Bloomberg Industries.
“Most antibiotics in use today are derived from natural products,” Cubist Chief Executive Officer Michael Bonney said in an interview. “They are nature’s way of arming bacteria in the soil so it can protect its homeland.”
The Lexington, Massachusetts-based company’s best-seller, the antibiotic Cubicin, drew $859.7 million in 2012 revenue, and analysts estimate it will top $1 billion in sales in 2014. The drug accounts for 93 percent of the company’s revenue. Cubist’s shares have more than doubled since 2010.
Cubicin has its roots in the sort of wilderness research that Barton lives for. The drug, also known as daptomycin, was discovered on Mount Ararat, the dormant volcano in eastern Turkey where, according to the Bible, Noah’s ark came to rest.
The medicine is effective against MRSA, or methicillin-resistant Staphylococcus aureus, a bug most commonly acquired in hospitals that has become resistant to other medicines. Cubicin is usually prescribed only after doctors have tried other options in order to curb the resistance that would arise were it to be used more widely.
Cubicin and Barton’s finds are part of a tradition of hunting for antibiotics in nature. In 1928, Alexander Fleming accidentally discovered penicillin when he found bacteria-killing mold growing in an open petri dish that had been left unattended. Subsequent discoveries in soil kicked off exploration efforts around the globe. The antibiotic vancomycin was found in 1953 in the jungles of Borneo. Cephalosporins, another class of bacteria-fighters, were first uncovered in 1948 in a sewer in Sardinia.
In its collaboration with Barton, Cubist adds samples she pulls from caves to its collection of strains that it then screens to find the best potential antibiotics, said Victoria Knight-Cononni, a senior scientist at Cubist who works on the company’s natural products research.
One type of bacteria Barton found in Lechuguilla acts as a predator to other bugs, she said. Studying those bacteria to understand their hunting methods may provide leads to developing new antibiotics.
“We’ve got it in the lab right now hunting other bacteria,” she said. “It grabs them and completely covers the prey bacteria.”
Cubist isn’t confining its antibiotic search to nature alone. The company spends more than half of its discovery budget on finding new antibiotics in nature and developed in the lab, according to Chief Scientific Officer Steve Gilman.
Antibiotic treatment delivered intravenously is a Cubist specialty. The company also has a partnership with Optimer Pharmaceuticals Inc. for the antibiotic Dificid, and has two other antibacterials in development. Its other marketed drug is Entereg, designed to speed recovery from surgery to remove a portion of the bowels, usually to treat colon cancer.
Cubist shares have gained 119 percent since January 2010, while revenue rose 46 percent from 2010 through 2012. The shares rose 1.9 percent to $41.55 at the close today in New York. Eleven analysts recommend buying the shares, while eight rate the company a hold. Their average price target is $50.92, or 23 percent higher than the current level, according to data compiled by Bloomberg.
“Cubist is really the first biotech company that investors have paid any attention to that has sold an IV antibiotic,” Greg Wade, an analyst with Wedbush Securities in San Francisco, said in a telephone interview. He owns shares of the company, and recommends buying the stock.
As Cubist forges ahead in antibiotics, many larger drug companies have pulled back. Hurdles at the U.S. Food and Drug Administration and the business reality of antibiotics -- slower uptake of new drugs to avoid resistance for as long as possible -- have curbed interest, reducing the number of large companies that engage in antibiotics development from 20 a few decades ago to just a handful currently, including AstraZeneca Plc and Merck & Co., said Brad Spellberg, an associate professor at the University of California, Los Angeles’s David Geffen School of Medicine.
“The return on investment for antibiotics was not acceptable for most companies,” Spellberg said. “The cost for development kept going up, the return they were getting back was going down and the risk of failing went up as the FDA made it almost impossible in most spaces.”
Last year, Congress passed a law to encourage development of new bug-fighting medicines, and the Infectious Diseases Society of America has started the “10 x ’20 Initiative” to bring 10 new antibiotics to market by 2020.
“It’s like death and taxes,” Manos Perros, head of the Infection Innovative Medicines unit at London-based AstraZeneca, said in a telephone interview. “These things are certain in life: bacteria will become resistant to anything we develop.”
AstraZeneca, whose London headquarters are a short walk from St. Mary’s Hospital where Fleming made his accidental penicillin discovery, is working on new methods for antibiotics development. The company is looking for new molecular targets and pursuing novel ways to work on known targets, Perros said.
The company has a collaboration with the Broad Institute in Cambridge, Massachusetts, to screen a library of chemicals that resemble natural products. It also looks for ways to make old drugs useful again by targeting the methods in which bacteria have developed resistance.
Merck, the second-largest U.S. drug company, also zeros in on known classes of antibiotics and tries to improve their activity so they are effective against resistant bugs, said Daria Hazuda, the worldwide head of antibiotics discovery research for the Whitehouse Station, New Jersey-based company. Merck is also searching for completely new kinds drugs, she said.
“It’s really remarkable to me that, historically, it’s been something like two decades since a completely novel new target approach has been discovered, validated and developed,” Hazuda said in a telephone interview. “Which really illustrates how challenging and difficult it is.”
At Cubist, scientists are hopeful that Barton’s caving expeditions will lead them in the right direction. The company first approached the British-born Barton to cave on its behalf after she was featured in a 2005 article in Outside magazine on “all-star innovators.”
She’ll soon be back exploring Lechuguilla’s more than 120 miles of tunnels, in one part rappelling down a 165-foot pit to gain access to the site’s hidden caverns. The pit wall descends for 30 to 40 feet, then opens out “almost like an old milk bottle,” she said.
“You’re in the middle of nowhere, just going down a thread like a spider,” Barton said. “You should be scared. If you have no fear of being there, you’re doing it wrong.”