TEXAS A&M (US) — Like rogue secret agents, some bacteria are able to surreptitiously shut themselves down to avoid an antibiotic attack.
“Through our research, we’re understanding that some bacteria go to ‘sleep,’ and that antibiotics only work on bacteria that are metabolically active,” says Thomas Wood, professor of chemical engineering at Texas A&M University.
“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.”
The research is reported online in the journal Nature Chemical Biology.
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 causing it essentially to shut down. 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 says, but “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.”
When encountering oxidative stress, the studied 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 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.
“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,” says Rebecca Page of Brown.
“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 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.”
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