As the old saying goes, what doesn't kill you only makes you stronger – and this could very well be the life motto of enterococci, superbug extraordinaire. A new study by scientists at the Broad Institute of MIT and Harvard suggests that not only do they predate the dinosaurs, they have also managed to survive everything that Nature has thrown at them, each time evolving to become more indestructible. Could deciphering their genetic blueprint bring us one step closer to defeating them?

Enterococci are gut-dwelling bacteria that are found in practically all living things, from worms to human beings. It is extremely hardy, so much so that it could be the inspiration for the next comic book superhero (or villain). Antibiotics, disinfectants, drying, starvation and toxic compounds such as sodium azide have little effect on it, and in the 1970s and 1980s, scientists started getting an inkling of how much of a problem it could be when enterococci emerged as one of the earliest antibiotic-resistant pathogens.

There are thousands of microbes that live in our gut, so how did this one particular bug evolve to become such a badass? In their quest for an answer, the study's researchers examined DNA from 24 species of enterococci, taken from the guts of various living things, including human beings. They then examined the genes, comparing the ones from existing enterococci to those of close relatives, to figure out which were unique to it and built an evolutionary timeline to estimate when these traits started to emerge.

"By analyzing the genomes and behaviors of today's enterococci, we were able to rewind the clock back to their earliest existence and piece together a picture of how these organisms were shaped into what they are today," explains geneticist and study author Ashlee Earl, group leader for the Bacterial Genomics Group at the Broad Institute of MIT and Harvard. "Understanding how the environment in which microbes live leads to new properties that could help us to predict how microbes will adapt to the use of antibiotics, antimicrobial hand soaps, disinfectants and other products intended to control their spread."

What emerged from this analysis reveals a fascinating origin story that goes all the way back to more than 400 million years ago.

Bacteria have been around since the dawn of time. The ancient oceans were teeming with all kinds of microbes and enterococci's forebears were among them, living in the guts of prehistoric aquatic creatures. Their peaceful existence was given a jolt when the Cambrian Explosion happened and as some of the oceans' critters started taking their first tentative steps on land around 100 million years later, they brought along with them the bacteria in their intestines, among them – you guessed it – enterococci.

This transition from water to land was a test of enterococci's survival instincts and it rose mightily to the challenge, evolving to survive its new and harsh environment. Unlike the moist, nutrient-rich waters of the sea, land-based environments are harsher and normally, intestinal microbes dry out and die when they are excreted from their host's body. Not enterococci.

All the strains that were sampled in the study – including those not found in hospitals – were found to be naturally resistant to dryness, starvation, disinfectants and many kinds of antibiotics – traits that the researchers believe were also shared by their ancestors. In fact, when they compared the genomes of these bacteria, they found that every time new species of animals appeared during key evolutionary points such as the End Permian Extinction, they were always accompanied by the emergence of new species of enterococci.

The researchers suggest that the bacteria's unique genes helped them thrive in their new environment by strengthening their cell walls, thus enabling them to withstand the dry conditions of land and (unhappily for us) making them impervious to disinfectants and antibiotics.

Today, antibiotic-resistant enterococci are responsible for a range of illnesses in hospitals, including bloodstream, surgical site and urinary tract infections. What makes this so worrying is that some strains have become resistant to vancomycin, an antibiotic of last resort that is given when all other treatments fail. The very sick are the most vulnerable to the bacteria and according to the Centers for Disease Control and Prevention, these vancomycin-resistant strains account for about 20,000 (or 30 percent) of enterococcus infections among hospitalized patients, with more than 1,000 cases ending in death each year.

Could this new insight into their genetic blueprint help scientists cripple it? The researchers believe so. "We now know what genes were gained by enterococci hundreds of millions of years ago, when they became resistant to drying out, and to disinfectants and antibiotics that attack their cell walls," says study leader Michael Gilmore, director of the Harvard Infectious Disease Institute.

"These are now targets for our research to design new types of antibiotics and disinfectants that specifically eliminate enterococci, to remove them as threats to hospitalized patients," adds his colleague Francois Lebreton.

The study was published in Cell Reports.

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