Nice bacteria finish last
Altruism is alive and well in bacterial populations, according to new linkurl:research;http://www.nature.com/nature/journal/v467/n7311/full/nature09354.html in __Nature__, which found that a few altruistic bacteria help their neighbors withstand the assaults of antibiotics, even at a cost to themselves. Image:flickr/celerity59Researchers from Boston University found that a minority of resistant bacteria help their susceptible neighbors survive by producing and sharing high amounts of the signali
Altruism is alive and well in bacterial populations, according to new linkurl:research;http://www.nature.com/nature/journal/v467/n7311/full/nature09354.html in __Nature__, which found that a few altruistic bacteria help their neighbors withstand the assaults of antibiotics, even at a cost to themselves.
Researchers from Boston University found that a minority of resistant bacteria help their susceptible neighbors survive by producing and sharing high amounts of the signaling molecule indole, which guards cells against oxidative stress and helps them flush out the antibiotic. But by doing so, they have fewer resources left for their own growth.
"Bacteria in a population can function as a multicellular organism of sorts -- where mutants that acquire a mutation affording resistance to the antibiotic will share a signaling molecule, indole -- helping out the more susceptible members of the population," linkurl:James Collins,;http://www.bu.edu/bme/people/primary/collins/ last author of the paper, said.
"This is very significant work," said linkurl:Thomas Wood,;http://www.che.tamu.edu/groups/Wood/ a biochemical engineer at Texas A&M University who was not involved in the study. "It's the first time anyone has shown that indole plays that kind of role."
The researchers were originally interested in understanding how antibiotic resistance arises in bacterial populations. They designed an experiment that allowed them to grow E. coli
in a bioreactor exposed to increasing daily rations of the broad-spectrum antibiotic norfloxacin.
Each day, they would take small samples of the population and test their resistance to the antibiotic. But they found that the majority of these small samples did not survive norfloxacin as well as they had when they were part of the larger colony.
"We were surprised to discover that in fact most of the isolates were significantly lower in resistance than the population as a whole," Collins said.
Every once in a while, however, the team managed to isolate a small group of bacteria that fared better than the larger group. Although these highly resistant strains accounted for less than one percent of the original population, the researchers realized they were bearing the brunt of antibiotic defense.
"In general, we've always believed that the guy that gets the [antibiotic resistance] mutation survives and everyone else dies," Collins said. "What we show is that the guy that gets the mutation pops up and helps everybody else."
The mutations in these resistant strains -- as whole genome sequencing later revealed -- occurred in genes previously known to afford resistance to the antibiotic.
But there was something else different about them as well. By looking at the proteins they were expressing, the team found that these lucky cells were the only ones producing tryptophanase -- an enzyme that catalyzes the production of indole by degrading the amino acid tryptophan.
Under normal conditions, all E. coli
cells produce tryptophanase, and therefore indole, Collins explained. But when they're really stressed, as they are when bathing in antibiotics, they halt the production of the enzyme.
It seems then, that the few cells that manage to acquire resistance to the antibiotic are not stressed by the antibiotic anymore, and therefore it's business as usual for them -- they keep producing and secreting indole.
It's been known for a decade that indole, when it accumulates outside of cells, regulates the expression of genes involved in drug resistance. Specifically, it turns on cells' efflux pumps, which serve to flush out antibiotics and other drugs, and activates oxidative stress defense pathways.
"This oxidative stress contributes significantly to the killing effects of the antibiotics," Collins said. "It appears that indole is slipping on some level of defense against this."
By pumping out indole into the medium, the resistant bacteria are essentially doling out life rafts to the vulnerable population -- allowing them to float on when they would otherwise most likely die.
"It buys them time," Collins said. "So now it's likely that a number of them will develop mutations that would make them resistant to the antibiotic strains as well."
But producing indole comes at a cost to this small group of cells. When the researchers engineered the resistant E. coli
to be unable to produce tryptophanase, and consequently indole, they found they grew better and faster, even in the presence of antibiotics.
This suggested that production of this molecule takes a toll on their competitiveness.
"To produce a protein requires utilizing energy and resources which otherwise can be used for your own growth," Collins explained.
In the paper, Collins and his colleagues likened this mechanism to "kin selection," where individuals of a species work to benefit the group, and not necessarily themselves.
"What's surprising to me is that the minority of these cells can make enough indole to activate other cells in the population," said linkurl:Philip Rather,;http://www.microbiology.emory.edu/rather_p.html a microbiologist at Emory University, who was not involved in the study.
Rather's lab actually discovered the extracellular signaling properties of indole back in 2000. "You need a high concentration of indole to have this population-based effect," he said. He believes the indole produced by the few resistant cells in itself is not enough.
Instead, because indole is known to activate its own production, Rather believes the indole from the resistant cells in turn activates the production of tryptophanase in the rest of the population, thus amplifying the concentration of indole.
"So this small number of cells starts a chain reaction," he said.
Because of this communal effect, drugs that block the indole pathway could present a powerful complementary tool to antibiotics. "This would make them stronger and hold off the emergence of resistance," Collins said.
H.L. Lee, et al., "Bacterial charity work leads to population-wide resistance," Nature, 467:82-6, 2010.
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[10th March 2003]