January / February 2017

Where will New Antibiotics Come From?

Scott Fotheringham, PhD

William Fenical is frustrated that the pharmaceutical industry hasn’t developed new antibiotics for more than 20 years. Without them, it will be impossible to check the surge of superbugs—antibiotic-resistant infectious agents such as methicillin-resistant Staphylococcus aureus (MRSA)—that result in over two million infections in the United States annually, with more than 23,000 fatalities.

“The industry is no longer interested in antibiotic development,” says Fenical. “Some pharmaceutical companies are manufacturing antibiotics profitably, but the R&D side is nonexistent and the industry doesn’t have the personnel with deep experience.” Fenical is a professor at the Center for Marine Biotechnology and Biomedicine at the Scripps Institution of Oceanography in San Diego, California. “The price of antibiotics is so low that there isn’t massive profit in treatments. Industry decided to get out of this field and instead work on areas that are more lucrative, like drugs for blood pressure, hepatitis, and cancer.”

The job of finding candidates has fallen to academics like him. Their preferred method is bioprospecting, which is the discovery and commercialization of drugs found in plants, animals, and microbes. Almost all of the 120 antibiotics that are currently approved—from penicillin to vancomycin—were found in soil microbes this way.

“More than 60% of all small-molecule drugs were found by bioprospecting,” says Eduardo Esquenazi, founder and CEO of Sirenas LLC, a company that screens marine microbes for novel antibiotics and cancer drugs.

These days, researchers like Esquenazi are taking a fresh approach: looking in the world’s oceans. At the time the current arsenal of drugs was being discovered, nobody thought to look in the sea. Sirenas, which partners with the Bill & Melinda Gates Foundation, has discovered an antimalarial in an algae living in a salt pond in the Chilean desert.

The price of antibiotics is so low that there isn’t massive profit in treatments. Industry decided to get out of this field.

“There’s never been a better time to bioprospect,” says David Sherman, professor at the Life Sciences Institute at the University of Michigan. “Methods are getting cheaper, faster, and better every year.”

Sherman’s lab gathers marine sediments from coral reefs and habitats that are high in biodiversity and that can contain as many as a billion microbes in every cubic centimeter. Samples come only from countries, like Costa Rica, that provide legal access and permission to take samples back to the United States. Divers bring back collections of spores that are isolated and screened for activity against pathogens to identify candidates, then isolate and characterize bioactive compounds. These scaffold molecules are then chemically modified to optimize their antimicrobial activity.

“Once we identify the compound’s target, we hope to make it more potent through biochemical modifications,” says Sherman. “We use sequencing technology to bring in genomics and bioinformatics to determine which molecules from which organisms contain biological activity.”

One exciting development in Sherman’s lab is the discovery of a molecule that inhibits the formation of biofilms, which are produced by some bacteria, and are a source of hospital-acquired infections. The lab, along with its pharmaceutical partner company, will then engineer the strain to make more of the bioactive compound.

“I’m finding the industry much more open-minded about getting back into natural products,” says Sherman. “Big pharma got out of it 20 years ago and now they’re realizing that that was a big mistake. It’s becoming a much more favorable atmosphere for discovering new natural product molecules.”

Antibiotic discovery may be happening, but getting these compounds to market is another matter. Esquenazi points out that while nature is the best source of antibiotics, it is costly and time consuming to cast a wide enough net to find them. This is the main reason that big pharma exited antibiotic discovery in the early 1990s. And Fenical doesn’t see governments doing much to solve this pressing problem.

“Beginning in the 1970s, government agencies in the United States and Canada accelerated funding for cancer research and now we have successful treatments,” says Fenical. “Despite the massive threat of infectious diseases, they haven’t created similar programs for antibiotic research.”

His lab at Scripps has discovered six antibiotics, one of which, anthracimycin, is potent against MRSA. “We’ve shown that it works in animals, we know the chemical structure, and we’ve proved the mechanism of action,” says Fenical. Yet the lab can’t find an avenue to develop it. “Nobody is out there with the kind of preclinical money to get it into Phase I. We’ve had to publish its structure and mechanism of action and hope that someone will pick it up.”

He cautions that time is of the essence: “We’re in crisis mode.”

If we don’t do something soon, more people will die of infectious diseases than cancer by 2025.”