Scientists Find a Weak Spot in Some Superbugs' Defenses

In 2004, a 64-year-old woman in Indiana had a catheter put in to help with dialysis. Soon after the procedure, she came to a local hospital with low blood pressure and what turned out to be a dangerous antibiotic-resistant infection from a bacteria called Enterococcus faecalis. Today, that woman’s blood samples helped solve a long-standing mystery: how this deadly bacteria neutralizes the most powerful antibiotic used to fight it. This mechanism could help scientists find new ways to fend off perhaps the biggest scourge facing health care today.Antibiotic-resistant infections are caused by microbes that have evolved immunity to the drugs that are supposed to destroy them, sometimes leaving doctors with no good treatment options. The Centers for Disease Control and Prevention estimate 2.8 million such infections happen in the US every year, killing more than 350,000 people. The World Health Organization calls such infections a “global crisis” that could cause 10 million deaths worldwide by 2050.
After the patient in Indiana returned to the hospital, doctors sampled her blood and tested various antibiotics to see what might cure her infection. The strain she was infected with was already resistant to the antibiotic vancomycin, which was traditionally considered the treatment of last resort. But the bacteria that were making her sick were susceptible to a powerful new drug, approved by the FDA just a year before, called daptomycin. With a prescription for daptomycin, the patient improved enough to go home.

But two weeks later, the woman was back in the hospital again, this time with a high fever. Nothing her medical team tried worked, and the woman died.

Enterococcus isn’t an inherently dangerous bacteria; most humans have some living in their gut. But some enterococcus strains have evolved into a virulent form, called vancomycin-resistant enterococcus, or VRE, that affects more than 540,000 Americans every year. They are especially prevalent in hospitals, where they flourish among patients with weakened immune systems, like the Indiana woman. Patients who have been taking antibiotics and don’t have a healthy population of other gut bacteria are also susceptible.
A study out today in the Proceedings of the National Academy of Sciences, though, offers new hope—along with clues about how drug developers might fight back against this foe. “Hopefully the paper demonstrates how incredibly clever a single cell can be,” says lead author Ayesha Khan, a doctoral student at the University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences.

VRE bacteria reproduce by pinching in at the center and dividing into two separate cells. Daptomycin fights VRE by binding to its cell membrane right at that center point, which disrupts its ability to divide, among other things.

After the patient in Indiana died, doctors compared a sample of her blood with one they’d taken weeks earlier, when she first came to the hospital. They discovered that the daptomycin-resistant strain had a new mechanism that reorganized the cell. Daptomycin could no longer attach and halt the bacteria’s cell division. “They’re literally remodeling and restructuring the barrier to distract the antibiotic from its target, which is a very, very intelligent mechanism,” says Khan.
Khan and her colleagues were puzzled that the cells somehow knew when to reorganize their membranes to resist the daptomycin. Khan noticed these drug-resistant strains had a lot of the protein LiaX both on the cell membrane and outside the cell, so she zeroed in on it.

LiaX, the research team found, is an alarm system. The protein binds to daptomycin, sending a signal back telling the cell that it’s time to reorganize. This same mechanism also helps VRE ward off the human immune system, they found, which might contribute to its deadly nature.