Wonder drug’s sticky secret weapon

PRINCETON (US)—New research on proteins reveals why some tried-and-true antibiotics are able to fend off bacterial strains so effectively. The drugs work like hair in a drain, simply plugging things up.

The discovery, by a team from Princeton University, also uncovers how one protein protects against cell death, shedding light on a natural cancer-fighting process.

Thomas Silhavy, the Warner-Lambert Parke-Davis Professor of molecular biology at Princeton, and graduate student Johna van Stelten, working with two Swiss researchers, had been studying the mechanism by which proteins—from antibodies to hormones—are produced in bacteria’s cytoplasm, the gooey substance that makes up the cell’s interior, and then transported where they are needed. The spaghetti-like proteins exit the bacteria’s cytoplasm through microscopic tubes known as translocators.

“Proteins go through the translocator, like a piece of spaghetti through a hole,” Silhavy explains. “But if you can imagine if you were to tie knots in the spaghetti, it wouldn’t be able to get through; it gets stuck.”

Silhavy and van Stelten are the first to observe what happens next. The bacterial cell actually attacks the jammed translocator, decimating it.

They then wondered what might happen if antibiotics were introduced into the cell cytoplasm to purposely thwart bacteria.

The scientists found that two types of antibiotics that have been in use for the past 50 years—tetracycline and chloramphenicol—cause the ribosomes, cell’s protein-producing machines, to stop midway through the process of making proteins, leaving partially constructed proteins stuck to the ribosome, jamming the bacteria’s translocator.

“This is very similar to plugging the translocator with a folded protein and, sure enough, this also causes translocator destruction,” Silhavy says. “It’s like putting an anchor on the spaghetti instead of a knot. They are stuck and dead forever.”

The current study provides an explanation as to why the antibiotics are so adept at killing some kinds of bacteria more quickly than others. Translocators are essential for life and, if some bacteria have fewer translocators from the start, then they are more vulnerable to such an attack.

“While it has been known for many years that these antibiotics work by inhibiting bacterial protein synthesis, it was not clear why some bacteria in a population appeared more susceptible than others,” van Stelten says. “Our work has identified a new reason why these antibiotics are lethal to bacteria that may help explain these earlier findings.”

The researchers made their discovery not because of a new piece of equipment or a new technique. “Like the vast majority of advancements in science and medicine, we happened upon this remarkable answer through basic research,” van Stelten notes.

“If we are to have any hope of outpacing the antibiotic resistance obtained by bacteria, it is paramount that we fully understand the mechanism of action of the antibiotics we currently use,” van Stelten says. “Unfortunately, this is often very difficult as evidenced by the fact that, 50 years on, we are still learning new things about them.”

Their work also produced another important result. When the translocators in bacteria became jammed by errant proteins, the researchers observed that the translocators emitted a molecular signal—a stress response—that called in a destructive enzyme known as the FtsH protease. Under normal circumstances, the FtsH protease chops up the jammed translocators, contributing to cell death.

The scientists found, however, that when they increased the amount of YccA, a protein that is present in the bacterial cell, YccA proteins protected the translocators from the FtsH attackers. YccA, it turns out, is very similar to a human protein known as Bax Inhibitor-1 (BI-1) that is of great interest to cancer researchers because cancer proliferates when it malfunctions.

“We have determined how YccA works in preventing stress-induced death in bacteria,” van Stelten says. “We hope this new information will shed light on the mechanism of BI-1 in humans.”

Researchers from the University of Geneva in Switzerland contributed to the research, which was supported by the National Institute of General Medical Sciences of the National Institutes of Health, the New Jersey Commission on Cancer Research, the Canton de Geneve and the Swiss National Science Foundation.

Princeton University news: www.princeton.edu/main/news/