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Scientists find a weak point in the defense of some superbugs

In 2004, a 64-year-old woman in Indiana had a catheter introduced to help with dialysis. Shortly after the procedure, she was admitted to a local hospital with low blood pressure and a dangerous antibiotic-resistant infection by a bacterium called Enterococcus faecalis . This woman's blood tests today helped solve a long-standing mystery: how this deadly bacterium neutralizes the strongest antibiotic it was used to combat. This mechanism could help scientists find new ways to ward off perhaps the biggest scourge of today's healthcare system.

Antibiotic-resistant infections are caused by microbes that have developed immunity to the drugs that they are supposed to destroy good treatment options. The Centers for Disease Control and Prevention estimate that in the US, 2.8 million such infections occur each year and more than 350,000 people die. The World Health Organization calls such infections a "global crisis" that could cause 1

0 million deaths worldwide by 2050.

After the patient returned to the hospital in Indiana, doctors took a blood sample and tested various antibiotics to find out what could cure their infection. The strain that infected her was already resistant to the antibiotic vancomycin, traditionally considered the last treatment. But the bacteria that made them sick were susceptible to a new drug called daptomycin, which had been approved by the FDA a year earlier. With a prescription for daptomycin, the patient got better enough to go home.

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

Enterococcus is not a naturally dangerous bacterium. Most people live in their intestines. However, some enterococcal strains have developed into a virulent form known as vancomycin-resistant enterococcus or VRE, affecting more than 540,000 Americans annually. They are particularly common in hospitals, where they thrive in immunocompromised patients such as the Indiana woman. Patients who have taken antibiotics and do not have a healthy population of other intestinal bacteria are also susceptible.

However, a study published today in the Proceedings of the National Academy of Sciences offers new hope – along with clues as to how drug developers could defend themselves against this enemy. "Hopefully, the work demonstrates how incredibly smart a single cell can be," says senior author Ayesha Khan, a graduate student at the University of Texas, Anderson Cancer Center.

The multiplication of AER bacteria takes place by pinching bacteria's center and dividing it into two separate cells. Daptomycin fights VRE by binding to its cell membrane at exactly this point, which, among other things, impairs the ability to divide.

After the patient died in Indiana, doctors compared a blood sample to one she had 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 was unable to attach and stop the cell division of the bacteria. "They literally rebuild the barrier and restructure it to distract the antibiotic from its target, which is a very, very intelligent mechanism," says Khan.

Khan and her colleagues were confused that the cells somehow knew when to reorganize their membranes to resist daptomycin. Khan noted that these drug-resistant strains had high levels of protein LiaX both on the cell membrane and outside the cell, so they focused on it.

LiaX, according to the research team, is an alarm system. The protein binds to daptomycin and sends back a signal telling the cell that it's time to reorganize. The same mechanism also helps VRE defend the human immune system, which could contribute to its deadly nature.

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