Scientists have discovered yet another way that single-celled organisms have outsmarted us.
The tiny bacteria that live inside our guts have an ingenious way of withstanding the onslaught of antibiotics we throw at them, said a report in the journal Science. The two-part system allows bacterial cells to stay alive until another bacterium can deliver a lifeline, packaged in a snippet of DNA.
Microbes 1, Humans 0.
"I'm afraid our findings are great news for bacterial cells — not so good for us," said study leader Christian Lesterlin, a researcher in the Molecular Microbiology and Structural Biochemistry program at Université Lyon in France. Lesterlin and his colleagues knew that superbugs could repel even our most modern medicines. What they didn't know was how they managed to pull it off.
"These are amazing abilities they have, to be able to adapt and survive in harsh environments," he said. "The more we understand about it, the more we can do for human health."
For most of human history, bacteria have had their way with us. Though some of them are helpful, others cause dangerous diseases like pneumonia, cholera and meningitis. The bacterium Yersinia pestis wiped out roughly 20% of the world's population in the mid-1300s during the pandemic known as the Black Death.
When scientists first developed antibiotics in the early 1900s, humans enjoyed the upper hand — for a while. Some of the drugs target the machinery that maintains a bacterium's all-important cell wall. Others rob bacteria of the proteins they need to carry out essential functions or damage the DNA needed to reproduce.
It took just a few decades for the first drug-resistant strains to appear. Since then, the invention of each new antibiotic invited a jeering reply.
Doctors responded by prescribing another antibiotic drug, and another. Then two drugs together. Then three. Now there are strains of Escherichia coli, Klebsiella pneumoniae, acinetobacter and enterococcus that have evolved to overcome almost every medicine thrown at them.
So scientists are racing to understand superbugs' tactics. Among the most urgent questions is this: How does antibiotic resistance spread between bacteria cells, even — or especially — in the presence of antibiotics that are designed to knock them back?
Bacteria know better than to wait around for a random mutation in their DNA that will protect them from antibiotics. For some drugs, only about 1 in 10,000 bacteria will develop resistance that way. For other drugs, only about one in a billion will do so.
Luckily for bacteria, they have plasmids at their disposal. These are circular snippets of DNA, and they can include genes that carry instructions for repelling specific antibiotics. Bacteria can swap useful plasmids with one another while socializing together in the human gut.
Lesterlin's team wanted to visualize exactly how the exchange worked. They put a regular strain of Escherichia coli bacteria in one petri dish and a strain that is resistant to the antibiotic tetracycline in another dish. Then they saturated both plates with tetracycline.
Logic suggested the bacteria cells lacking the ability to resist the drug would die. Instead, they went to sleep. After several hours, the researchers combined the contents of the two dishes. Less than two hours later, the plasmid produced a protein called TetA resistance factor, which makes bacteria impervious to tetracycline. That was "shockingly counterintuitive," Lesterlin said, since tetracycline blocks the production of proteins by binding to the machinery required to make them.
How could bacteria get away with producing drug-resistance proteins right there in the presence of a protein-inhibiting drug?
As the hosts on QVC might say, one can never have too many accessories.
That's especially true for the AcrAB-TolC multidrug efflux pump, which sits on the cell's outer membrane and ejects various toxic antibiotics that have invaded the cell's interior.
The pump is not sufficient to keep the cell thriving amid a surge of antibiotics. But it buys vital time for the groggy cell to acquire a plasmid with a resistance gene.
In the experiments, the pump kept tetracycline levels low enough to give the cell a chance to translate the resistance gene into a version of the TetA protein that was immune to the antibiotic. Then that TetA protein took the reins in sustaining the newly drug-resistant cell, which went on to grow and multiply. "Thanks to the multidrug efflux pump, bacteria have the ability to remain dormant — not quite dead but not quite alive — just waiting for a little help from a neighbor," Lesterlin said.
With the new understanding of plasmid transfers, scientists can try to create treatments that attack the multidrug efflux pumps that allow resistance to spread. "Bacteria have multiple weapons — you can't just shut down one weapon and expect to succeed," said Shaun Yang, assistant medical director of the Clinical Microbiology Laboratory at UCLA.
For now, scientists remain locked in a race that could mean life or death for all organisms involved. The United Nations warns that, without action, drug-resistant infections could kill 10 million people annually by 2050. That's a public health nightmare, but hardly a surprise. After all, bacteria have a few billion years of guerrilla warfare under their belts.