'Going off the grid' helps some bacteria hide from antibiotics

Going "off the grid," like rogue secret agents, some bacteria avoid antibiotic treatments by essentially shutting down and hiding until it's safe to come out again, says Thomas Wood, professor in the Artie McFerrin Department of Chemical Engineering at Texas A&M University.

This surreptitious and elaborate survival mechanism is explained in the online April edition of Nature Chemical Biology, which details the research of Wood and his post doctoral student Xiaoxue Wang along with colleagues Breann Brown, Wolfgang Peti and Rebecca Page of Brown University.

"Through our research, we're understanding that some bacteria go to 'sleep,' and that antibiotics only work on bacteria that are metabolically active," Wood explains. "You need actively growing bacteria to be susceptible to antibiotics. If the bacterium goes to sleep, the antibiotics, no matter what they do, are not effective because the bacterium is no longer doing the thing that the antibiotic is trying to shut down."

It's an alternative method for survival, Wood says, that starkly contrasts the widely studied genetically based approaches utilized by bacteria through which bacteria gain resistance to antibiotics as the result of mutations experienced throughout time. This mutation-free response, however, demonstrates that some bacteria need not mutate to survive external stressors, Wood says.

Instead, when triggered by an external stressor such as an antibiotic, a bacterial cell can render itself dormant by triggering an internal reaction that degrades the effectiveness of its own internal antitoxins, Wood explains. With its antitoxins damaged, the toxins present within the bacterial cell are left unchecked and damage the cell's metabolic processes so that it essentially shuts down, he adds.

It's self-inflicted damage but with a purpose.

"The cell normally doesn't want to hurt itself; it wants to grow as fast as possible," Wood states; the raison d'être for a cell is to make another cell," Wood says. "However, most bacteria have this group of proteins, and if this group was active -- if you got rid of the antitoxins -- this group of toxins would either kill the cell or damage it."

Specifically, Wood and his colleagues found that when encountering oxidative stress, their bacterial cells initiated a process through which an antitoxin called MqsA was degraded, in turn allowing the toxin MqsR to degrade all of the cells' messenger RNA. This messenger RNA, Wood explains, plays a critical intermediate role in the cell's process of manufacturing proteins, so without it the cell can't make proteins. With the protein-manufacturing factory shut down, the bacterial cell goes dormant, and an antibiotic cannot "lock on" to the cell. When the stressor is removed, the bacterial cells eventually come back online and resume their normal activities, Wood says.

"It was the combination of the genetic studies at Texas A&M with our structural studies at Brown University that demonstrated that the proteins MqsR:MqsA form an entirely new family of toxin:antitoxin systems," Page says. "Remarkably, we have shown this system not only controls its own genes, but also many other genes in E. coli, including the gene that controls the response to oxidative stress."

This response mechanism, Wood emphasizes, does not replace the mutation-based approaches that have for years characterized cell behavior; it's merely another method in a multifaceted approach undertaken by bacteria to ensure survival.

"A small community of bacteria is in a sense hedging its bet against a threat to its survival by taking another approach," Wood says. "To the bacteria, this is always a numbers game. In one milliliter you can have a trillion bacterial cells, and they don't always do the same thing under stress.

"If we can determine that this 'going to sleep' is the dominant mechanism utilized by bacteria, then we can begin to figure out how to 'wake them up' so that they will be more susceptible to the antibiotic. This ideally would include simultaneously applying the antibiotic and a chemical that wakes up the bacteria. That's the goal -- a more effective antibiotic."