Back to basics: Combatting antibiotic resistance

Modern medicine, from cardiac surgery to chemotherapy, rests on a foundation of reliable antibiotics. But health authorities around the world warn that the effectiveness of antibiotics is under increasing threat from resistant bacteria. Mark Brynildsen, an assistant professor of chemical and biological engineering, is seeking solutions to this problem through new ways to combat dangerous bacteria.

Researchers in his lab are combining several approaches: disrupting bacteria’s ability to infect people; unravelling bacteria’s ability to survive antibiotics and other forms of stress; and preventing formations called biofilms, which some bacteria use to protect themselves from outside threats like antibiotics. The lab is also pursuing fundamental research into the interaction between bacteria and their hosts.

Some of Brynildsen’s recent work has focused on persisters, bacteria that survive in the face of an onslaught by antibiotics. Unlike antibiotic-resistant bacteria, which are genetically different than normal strains, persisters are genetically identical to ordinary bacteria but somehow survive a course of treatment.

“Persistence is like an insurance policy, where a small portion of cells enter dormancy and sacrifice their ability to replicate in order to survive stress at a future time,” Brynildsen said.

Bacterial persistence is a serious problem because scientists believe that it plays a key role in chronic infections. But the mechanism behind persistence is complex and not fully understood.

In one recent project, Brynildsen’s team used a combination of experiment and modeling to elucidate a pathway to persistence that was initiated by nutrient transitions.

The team, which also included graduate student Stephanie Amato and post-doctoral associate Mehmet Orman, traced one path responsible for forming persisters, but found that the metabolic stress actually activated several different pathways at once.

“These data suggest that not only do native stresses generate persisters, but also that different persisters can arise from the same stress,” they wrote in an article in the journal Molecular Cell.

Brynildsen’s research team has also examined development of bacterial persisters in biofilms, groups of bacteria that stick together and adhere to a surface. Biofilms often play a role in the recurrence of infections after antibiotic treatment; in part because they allow for the development of persisters. Therefore, understanding the link between biofilms and persisters could be a key to developing more effective treatments for many chronic and recurring infections.

“Despite this importance, the mechanisms of persister formation in biofilms remain unclear,” Brynildsen and Amato wrote in a recent article in the journal PLoS One.

In the article, the researchers note that identifying the role biofilms play in persistence is complicated by the many variables that biofilms introduce: slower growth; the presence of toxic byproducts of bacterial metabolism (known as oxidative stress;) and a bacterial group response to population density called quorum signaling.

Although the researchers noted that these factors make it likely that persisters develop in biofilms for a number of different reasons, they took a closer look at nutrient transitions in biofilms and their ability to generate persisters.

“Nutrient transitions are abundant in biofilms, as cells at the periphery consume favorable substrates and leave less favorable substrates and waste products available to cells deeper in the film,” they wrote.

The researchers developed a method to test the effect of nutrient transitions on persistence, found that such stresses do form persisters in biofilms, and identified the underlying pathway.

“If we can better understand the emergence of persistence, we can begin to address the very difficult problem of chronic and recurrent infections,” Brynildsen said. “There is a lot of work ahead, but we think we are on a promising path.”