Researchers receive $9 million grant to develop novel platform to quickly identify new antibiotics

In September 2014, President Obama issued an executive order for "Combating Antibiotic- Resistant Bacteria." Why the urgency? The Centers for Disease Control and Prevention, the order noted, "estimates that annually at least 2 million illnesses and 23,000 deaths are caused by antibiotic- resistant bacteria in the United States alone."

This month, a team led by Northeastern University Distinguished Professor of Biology Kim Lewis received a five- year, $9 million grant from the National Institutes of Health's National Institute of Allergy and Infectious Diseases to develop a novel platform to translate the president's order into action.

The award will enable the team to expand on the pioneering research of Lewis and Distinguished Professor of Biology Slava Epstein. The pair used an innovative method to grow "unculturable" bacteria in the lab, leading to the discovery of a new antibiotic that kills pathogens without encountering any detectable resistance. Called teixobactin, the antibiotic eliminated the superbug MRSA, or methicillin- resistant Staphylococcus aureus, in mice as well as numerous other pathogens.

The new platform will facilitate quick identification of new antibiotics such as teixobactin, says Lewis, who is also director of the Antimicrobial Discovery Center. "There are a number of bottlenecks in natural product discovery," he says. "Our aim is to resolve these bottlenecks and improve our efficiency by a couple of orders of magnitude."

Indeed, as the authors write in a paper they recently submitted, the platform "has strong potential to return us to the golden age of antibiotic discovery."

The well runs dry

In that golden age, researchers discovered new antibiotics by screening soil for microorganisms that produced compounds lethal to other pathogens. But that well essentially ran dry by the late 1960s, and the bacteria had acquired mutations that rendered them resistant to the once effective antibiotics.

Lewis and Epstein's breakthrough was in finding a way to tap into the 99 percent of soil- based microorganisms that won't grow in a lab. They used a small device developed by Epstein's group called the iChip that isolates and grows individual bacterial cells in their natural soil environment. The breakthrough led to Lewis and Epstein co- founding NovoBiotic Pharmaceuticals, in Cambridge, Massachusetts. Amy Spoering, PhD'05, who now works at NovoBiotic, is a co- investigator on the new NIAID grant. From the uncultured bacteria they identified 25 new antibiotics, among them teixobactin and lassomycin, which acts against Mycobacterium tuberculosis.

Still, says Lewis, the process left certain elements up to chance. "We had no idea whether the soil harbored interesting microorganisms or didn't," he says. "So then the obvious question became: Why not take a step back and screen the soils themselves before isolating individual bacteria?"

On the fast track to discovery

The new platform uses sophisticated genomic technologies and bioinformatics tools to do just that.

With co- investigator Karen E. Nelson, president of the J. Craig Ventor Institute, in La Jolla, California, the researchers will extract DNA straight from the soil samples and, using genetic sequencing, determine the diversity of the microorganisms within and identify each one by type.

"It's a one- step process," says Lewis. "Based on experience we will then know right away whether the soil contains the types of bacteria that have historically been linked to antibiotic production."

The initial soil samples, says Lewis, will come from Northeastern property, including that in Nahant, Massachusetts, home of the university's Marine Science Center.

Currently, once researchers identify a promising bacterium based on its ability to inhibit a pathogen, say, MRSA, they take an extract from it and chemically analyze the extract's characteristics. "It's a laborious process, an enormous bottleneck," says Lewis. "And the vast majority of things found in producing bacteria are junk. Finding a compound that's useful is like searching for a needle in a haystack."

The new platform fast- tracks the process. The extracts will be analyzed not chemically but biologically, displaying what genes the target pathogen expresses when treated with an extract containing an antimicrobial compound. "From that pattern of gene expression we can deduce the mode of action of the compound and make a call about its potential usefulness," says Lewis.

Finally, Lewis will test the selected compounds to map their mechanism of action in detail and then validate their effectiveness against a host of pathogens both in cell cultures and a mouse model.

"I think that we are going to find many novel antibiotics," says Lewis. "We are very excited about this opportunity."