Photograph courtesy Max Wisshak, speleo-foto.de
Published April 11, 2012
The bacteria coat the walls of the Lechuguilla cave system on rock faces some 1,600 feet (487 meters) below Earth's surface. Until recently, the microscopic life-forms had encountered neither humans nor modern antibiotics.
(Related: "Cockroach Brains May Hold New Antibiotics?")
That's because a thick dome of rock isolated the cave between four and seven million years ago. Any water that trickles through takes roughly ten thousand years to reach the cave's depths—which means the subterranean life has existed entirely in the absence of modern medicine.
While not infectious to humans, the cave bacteria can resist multiple classes of antibiotics, including new synthetic drugs. The discovery serves as an intriguing lead in the quest to understand how drug-resistant diseases emerge.
"Clinical microbiologists have been perplexed for the longest time. When you bring a new antibiotic into the hospital, resistance inevitably appears shortly thereafter, within months to years," said study leader Gerry Wright, a chemical biologist at McMaster University in Ontario.
"It's still a big question: Where is this coming from?" Wright said. "Almost no one thought to look at other bacteria, the ones that don't necessarily cause disease."
Growing "Superbug" Problem
Lechuguilla is one of the deepest and most extensive cave systems in New Mexico's Carlsbad Caverns National Park. With at least 130 miles (209 kilometers) of mapped passages, Lechuguilla is also the planet's seventh longest known cave.
(Also see photos of the world's largest cave, in Vietnam.)
In 1984 cavers began digging through rubble in an old mining pit and found an entrance to the cave, which they had suspected might be there. The cavers broke through in 1986 to unveil one of the last environments on Earth untouched by human activity.
The U.S. National Park Service strictly limits entry to the cave, but since 2008 the agency has allowed geomicrobiologist Hazel Barton of Northern Kentucky University and her team into the cavern to sample its microbial life.
"Hazel sampled sites clearly not touched by humans before. Because it's so pristine, you can see where people—all of the people—have walked," Wright said. "It's a serious stretch of the imagination to think any of the sites sampled have seen significant impact by anything from the surface."
Barton scraped off and bagged samples of biofilms—thick mats of bacteria—growing on the cave walls and delivered them to Wright's laboratory, where his team spent three years probing the samples for any signs of antibiotic resistance.
Disease-causing bacteria have grown increasingly resistant to many of the dozens of classes of antibiotics used to fight them. Such strains, often called superbugs, can immobilize, chew up, or block natural and synthetic antibiotic compounds.
Superbugs almost always appear in hospitals and on animal farms, where antibiotic use is prevalent. In these environments, intense evolutionary pressure pushes microbes to quickly develop resistance to multiple drugs.
But how this happens is a frustrating problem, Wright said, considering that studies suggest the preponderance of antibiotic-fighting genes should have taken thousands or millions of years to emerge.
The answer may lie in the fact that bacteria regularly exchange, receive, or steal genes from other bacteria in their environments. Many microbiologists therefore suspect that nonpathogenic bacteria are acting as a vast pool of ancient resistance genes waiting to be transferred to pathogenic bacteria.
"It's kind of a thesis at this point: These benign environmental organisms are the root of resistance," Wright said.
"There are so many of them with so many resistance genes that could move horizontally through populations," either via sexual reproduction, transfer through viruses, or absorption of genetic scraps.
Diversity of Drug-Flighting Genes
The cave finding builds on Wright's previous work, in which he found bacteria with resistance genes in primordial soils untouched by humans, normal soils, and permafrost, noted microbiologist Julian Davies of the University of British Columbia, who wasn't involved in the study.
Those findings intrigued skeptics, but Wright wanted firmer evidence that antibiotic resistance genes are ancient and not a new microbiological fad.
"Now he's found them in these pristine caves," Davies said.
Wright's team managed to grow 500 different kinds of bacteria from the Lechuguilla caves, but only 93 grew in a medium that allows testing for resistance to 26 different antimicrobial agents.
Of those 93, about 70 percent resisted three to four classes of antibiotics. Three of these strains are distant relatives of the bacterium that creates anthrax spores—they fought off 14 of the 26 antibiotics.
"I honestly didn't expect to see the sheer diversity of genes fighting all of these different antimicrobial compounds," study leader Wright said.
Which Came First: Antibiotics, or Resistance?
Davies noted that Wright's team removed bacterial strains from a foreign environment, grew them in laboratory conditions, and then showed genes that can fight antibiotics—so the result may be a fortuitous byproduct of genes never designed to battle antibiotics.
"This tells us antibiotic resistance genes are very old, but what it doesn't tell us is how they find their way into the hospital," Davies said.
Stuart Levy, a physician and microbiologist at Tufts Medical School, said Wright's study should help researchers better understand the origins of antibiotic resistance, but he also agreed with Davies' points.
"Is resistance providing additional protection to organisms down there in the cave? Maybe it's something that looks like antibiotic resistance but really isn't," said Levy, who wasn't involved in the work.
"It's an issue of which came first, the chicken or the egg? Did microbes generate the antibiotics down there, then resistance developed, or is it the other way around?" The cave bacteria, the thinking goes, may generate natural antibiotics during "chemical warfare" with their microbial competition.
Until researchers can further probe the new microbe strains' genetics—and find any natural antibiotics lingering in the cave—the work should put clinicians on alert, study leader Wright said.
"Imagine I'm a pharmaceutical company about to invest a billion dollars researching a single antibiotic," Wright said. "This tells us I should check first to see if there are trivial ways pathogens might become resistant by looking at microbes outside of the hospital."
The cave-microbes study was published April 11 in the journal PLoS ONE.
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