Breaching bacteria's tough outer membrane could be path to new antibiotics

July 18, 2018

A discovery about bacterial physics could point to a new way to develop antibiotics. The finding is likely to apply to approximately half of the world's bacteria — potentially including antibiotic-resistant strains — said K.C. Huang, Ph.D., senior author on the study, which was published today in the journal Nature.

undefinedHuang and his colleagues found that the outer layer of E. coli behaves very differently than scientists had previously believed. This microbe is what is known as a Gram-negative bacterium, one of two broad classes of bacteria that also includes the disease-causing microbes Salmonella typhae and Pseudomonas aeruginosa

All species of bacteria have a thick cell wall surrounding them that helps them maintain their shape in harsh environments such as the soil, bloodstream or human gut; Gram-negative bacteria also have a thin, outer membrane on top of that cell wall.

Most scientists thought that the outer membrane functioned like shrink wrap, Huang said, keeping important molecules inside the cell and toxic chemicals out, and that the cell wall acted more as armor or exoskeleton to physically protect the cells. But the study led by Huang, who is an associate professor of bioengineering and a member of the Allen Discovery Center at Stanford University, found that the outer membrane is far tougher than it appeared.

"The outer membrane is actually even more stiff than the cell wall," Huang said. "It makes a larger contribution to cell mechanics than the object that had been thought for decades to be the only thing that matters for bacterial mechanics."

That's important not only for scientists like Huang who are trying to understand cellular biophysics, but because current antibiotics focus on targeting the bacterial cell wall — and new antibiotic strategies are sorely needed. Due in part to overuse of antibiotics, resistant strains of bacteria are on the rise. In the U.S. alone, at least 23,000 people die every year because of infections with antibiotic-resistant bacteria

A missed opportunity

When Huang and his colleagues disrupted the E. coli bacterium's outer membrane, using either a genetic manipulation that weakened the membrane or a chemical that ripped it apart, the cells became incredibly sensitive to mechanical disruption. 

undefinedE. coli cells missing both their stiff outer membrane and their cell wall implode during division. A new study led by researchers at the Allen Discovery Center at Stanford University has found that the outer membrane of Gram-negative bacteria has important physical properties that had previously gone undiscovered. Movie courtesy of Enrique Rojas, Ph. D., and Nature.

"We've been missing out on this huge opportunity to target the outer membrane, not just to get drugs in, but to break down the cell structurally," Huang said. "You can make cells become so sensitive that a perturbation that normally the cell would ignore will kill every cell. It's a switch between life and death."

The outer membrane bears loads through large molecules that are able to link together to collectively have a similar property that gives water its surface tension — for the microscopic bacterium, that force is strong enough to keep it whole under stress. 

The researchers also found that more pathogenic strains of E. coli have more complex forms of this molecule that seem to make the cells even stronger. The outer membrane could thus be contributing to the bacteria's ability to survive and wreak havoc inside the human body, and the microbes may even be able to tune their stiffness based on their environment.

From E. coli to Salmonella

The Allen Discovery Center at Stanford is using systems biology to understand how Salmonella can survive inside the body and how to potentially disrupt that survival with new treatments. Salmonella is a food-borne, Gram-negative bacterium responsible for more than 200,000 deaths worldwide every year

The next step for Huang and his team is to see if Salmonella's outer membrane serves a similar function — and if it might prove a new target for antibiotics for that infection too. Huang is excited not only about the possibility of a new class of antibiotics, but the possibility of combinations of drugs that could target both the outer membrane and the cell wall, and could thus be much more powerful than either type alone. 

Antibiotic resistance arises when random mutations allow certain bacteria to escape being killed by the drug; those bacteria can then grow and take over the population. If a drug targets two different, important parts of the cell, the organism may be less likely to develop resistance.

For Huang, being able to work on these problems as part of the Allen Discovery Center has advanced his science in a number of ways. As a scientist who was traditionally focused on fundamental questions of biophysics, the funding for the center has enabled a new focus on infection and treatment, he said. And it's brought together a number of different experts working together on the very complex problem of human bacterial infections, which they are tacking in an integrated way that wouldn't be possible working alone.

"For me and my lab, those intellectual contributions are as important as the funding aspect itself," Huang said.

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