Among people with cystic fibrosis, nearly 90% experience growth of biofilms that build up in their airways and clog their lungs. Existing therapies can help affected individuals breathe easier but stop short of clearing the infections. Now, scientists think they understand why: the microbes behind these infections develop a characteristic known as 'persistence'. Unlike 'resistant' microbes that can grow in the presence of antibiotics, so-called 'persistent' microbes can only tolerate these antibacterial medicines when they are dormant, which often occurs when they are in biofilms. Some experts speculate that persistent bacteria are able to escape antibiotics by turning down their internal metabolic activity.

Reporting last December, scientists at Northeastern University in Boston discovered that airway infections in people with cystic fibrosis probably recur because the microbes in the lungs have mutations that allow them to evolve persistence, which sharply decreases the effectiveness of typically prescribed antibiotics such as ofloxacin, carbenicillin and tobramycin (J. Bacteriol. 192, 6191–6199, 2010). Part of the difficulty, according to lead author Kim Lewis of Northeastern University, is that these pathogens use many mechanisms to develop persistence, making it that much harder to come up with new drugs to eradicate them.

“This Hydra has many heads,” says Lewis. “Traditional, straightforward target discovery is not going to work.”

The Northeastern team is now looking toward alternative strategies to develop biofilm-busting medicines. The researchers hope to develop so-called 'prodrug' antibiotics that kill pathogens only upon internalization. This is an especially good choice for persistent pathogens because the drug needs only to permeate into these microbes—the medicines eliminate these pathogens by membrane or genome disruption. Such strategies already show great promise to treat persistent tuberculosis infections.

Not giving up: Kim Lewis wants to thwart persister cells. Credit: Mary Knox Merrill, courtesy of Northeastern University

Meanwhile, a group of researchers at Boston University School of Medicine believe that adding sugar to antibiotics might nudge persistent bacteria into a metabolically more active state and make them more susceptible to defeat by antibiotics. Reporting last month, James Collins and his team found that sugars made lab-grown Escherichia coli and Staphylococcus aureus biofilms more vulnerable to a certain class of antibiotics called aminoglycosides. And sugar stimulated over a 90% drop of bacterial load in antibiotic-treated mice suffering from catheter-associated infections (Nature 473, 216–220, 2011). In the future, Collins hopes to optimize his persister-busting regimen to clear these infections.

“We would like to expand the microbial arsenal,” says Collins, “and make the tools we already have more effective.”