BU researchers deliver one-two punch against wily bacteria

Collins is a MacArthur "genius" grant recipient who is best known for building a vibrating shoe insole that could help elderly people, who often have trouble with balance, walk sure-footedly.

But in recent years his laboratory has been studying the precise interactions between bacteria and antibiotics, in search of new ammunition for the escalating war against infections.

"We're currently in an era where we're having to rethink our antibiotics," said Dr. Deborah Hung, a core faculty member who studies infectious disease at the Broad Institute, a Cambridge genetics research center. "In the last five years or so, there's been this important renaissance that's been quite spearheaded by Jim Collins, to revisit this question: do we really know how antibiotics work?"

Infections that resist treatment or come back have become a major public health problem. Most people are familiar with resistance, when bacteria mutate into strains that are invulnerable to a particular drug. But in any population, there are also persisters, which slip into a dormant state that allows them to survive antibiotic attack. Such bacteria are still poorly understood, but are thought to play a role in a wide range of problems, from hard to treat biofilm infections that form on implanted medical devices, to tuberculosis.

"Persisters are very difficult to eradicate; they evolved to survive," said Kim Lewis, director of the Antimicrobial Discovery Center at Northeastern University. "Looking for ways to try to beat them is very important."

Lewis' laboratory recently found that persisters play an essential role in the infections that afflict cystic fibrosis patients. In work published last year in PLoS Biology, he found that administering a particular type of antibiotic can have the unintended effect of creating persisters, sending bacteria into a dormant state that allows them to survive a broad spectrum of drugs.

Ultimately, the goal of such research is to identify weak spots that might be targets for new kinds of drugs, or combination therapies that might boost the power of existing antibiotics.

Because persisters survive antibiotic treatment by shutting down, it seemed natural to try waking them up in order to finish them off. So Collins and a graduate student, Kyle Allison, concocted various cocktails of sugars and different classes of antibiotics to see whether they could jolt the persisters' metabolism awake.

To their surprise, they found that they weren't waking the bacteria up completely, but turning them on just enough to make them vulnerable to one class of antibiotics, called aminoglycosides.

It was a bit like flooring the gas pedal in a car and then seeing only one tire turn, said Floyd Romesberg, an associate professor of chemistry at the Scripps Research Institute, who was not involved in the research.

When Collins and Allison injected mice, infected with E. coli, with an antibiotic called gentamicin and a sugar called mannitol, they were able to knock down persister bacteria and stop the spread of infection.

"This is a neat study," Romesberg said. "There's been a real dearth of new antibiotic development in the past 40 years, and now basic science is coming in and reenergizing the field and coming up with smarter ways of going after killing bacteria."

Collins' laboratory is now testing whether a similar sugar and antibiotic cocktail might work against the bacteria that cause tuberculosis.

And it's not purely a matter of scientific interest. Two years ago, in the midst of this research, Collins' mother was hospitalized for a staph infection. She was put on intravenous antibiotics and got better -- only to see the same infection return again and again.

"It was frustrating for me to see this occur," Collins said. "But satisfying to think that we may now have a treatment that ... is very simple, very inexpensive, and is something that could be implemented quite readily."