New Weapon to Fight Drug Tolerant Bacteria

The key to battling drug-tolerant superbugs could be keeping them awake. New research into how bacteria go dormant, allowing them to evade drugs, could lead to a method to keep them from hiding.

Bacterial infections are often hard to eradicate because a small percentage of germs are dormant at any one time. These mysterious "persisters" duck antibiotics, then awaken and multiply again after drug treatments stop.

But the mechanisms of bacterial persistence are becoming clearer, and so are ways to combat the phenomenon. A new study in Science Thursday maps out the structure and function of one major dormancy-inducer in bacteria, a protein called HipA. And it suggests how another protein, HipB, neutralizes it.

"Now we know what HipA looks like and how it functions," said lead author Maria Schumacher, a biochemist at the University of Texas' M. D. Anderson Cancer Center in Houston. "We can try to develop more specific inhibitors against it."

Scientists could mine libraries of known compounds for more inhibitors or try to design them anew. Either way, unlocking HipA's secrets is a big step forward.

"Persistence has been underappreciated for some time as a mechanism for bacteria to evade antibiotics," said microbiologist Thomas Hill of the University of North Dakota School of Medicine and Health Sciences, who was not involved in the study. "This paper takes us one step closer to understanding what persistence is all about."

Persistent bacteria are different than antibiotic-resistant bacteria, which evolve as a population to withstand the action of a particular drug. Persistent bacteria aren't resistant to drugs; they just wait them out. Most antibiotics target growing bacteria, killing by forcing the germs to make toxic byproducts. But a dormant bug isn't producing anything, toxic or not. So it survives, rising again another day.

These drug-tolerant bacteria are a major health issue because they are common in biofilms, thin skins of microorganisms that coat surfaces and cause about 60 percent of infections in the developed world.

"Biofilms build up on medical equipment," said co-author Richard Brennan, also a biochemist at M. D. Anderson Cancer Center. "Cystic fibrosis patients have biofilms growing in their lungs."

The persistence phenomenon was identified during World War II, when doctors discovered that many bacteria remaining in the human body after a course of penicillin were actually susceptible to the drug. Persistence has proven difficult to investigate, however, because only about one in a million bacteria are dormant at any particular time.

In the new study, Schumacher's team found that HipA inactivates a compound involved in protein production. With their protein pipeline shut down, bacteria become dormant.

HipB counteracts HipA by latching onto it and locking it into a shape that prevents it from shutting down the protein production. And HipB also likely hides HipA away where the bacteria's DNA is stored, keeping the HipA from even encountering the protein-producing compound, which is found mostly in the membranes and cellular fluid.

This system is probably not confined to E. coli, making it an intriguing target. According to the study's authors, HipA occurs in many different pathogenic bacteria and likely plays a major role in the development of persistence.

Though the study sheds light on how bacteria become dormant, it doesn't clarify what spurs the phenomenon on — why HipB sometimes falls away and lets HipA work its soporific magic.

"It seems to happen randomly," Brennan said.

For Schumacher and her team, the next step is finding out what else HipA does, and looking for other compounds that may induce bacterial dormancy.

"There are other mechanisms for persistence that we'd like to investigate," Brennan said. "But it's still early days."

Schumacher and Brennan see their results as a validation of basic research — attacking interesting questions without necessarily knowing what practical applications will result.

"This is basic science at its best," Brennan said. "It's a discovery of how things work that has opened up new possibilities for research."

"A lot of people wonder where their tax dollars are going," Schumacher said. "But people are seeing more and more how important it is to understand biological processes on a mechanistic level."

Citation: "Molecular Mechanisms of HipA-Mediated Multidrug Tolerance and Its Neutralization by HipB." By Maria A. Schumacher, Kevin M. Piro, Weijun Xu, Sonja Hansen, Kim Lewis, Richard G. Brennan. Science Vol. 323, 16 January 2009.