Extraordinary pictures show what a common antibiotic does to E. coli

Path antibiotics Called polymyxins that penetrate bacterial armor have been discovered in stunning detail using high-resolution microscopy, which could help us develop new treatments. drug-resistant infections.

Polymyxins are usually used as a last resort against certain so-called gram-negative bacteria, which can cause infections such as pneumonia, meningitis and typhoid fever. “All three of the World Health Organization's top priority pathogens are gram-negative bacteria, and this is largely a reflection of their complex cell wall,” says Andrew Edwards at Imperial College London.

Around the inner cell of these bacteria is an outer surface layer containing molecules called lipopolysaccharides, which act as armor. We knew that polymyxins targeted this outer layer, but it wasn't clear exactly how they disrupted it and then killed the bacteria; and there was no reason why drugs doesn't always work.

Now Edwards and his colleagues have used biochemical experiments and atomic force microscopy, in which a needle just a few nanometers wide creates an image of the cell by determining its shape, to discover that one of two types of polymyxin used therapeutically, called polymyxin B, causes strange bumps to appear on the surface of the gram-negative bacterium. coli.

A few minutes after the protrusions appear, the bacterium begins to rapidly secrete lipopolysaccharides, which the researchers found in the solution in which it was located.

The researchers say the presence of the antibiotic causes the bacterium to try to put more and more lipopolysaccharide “building blocks” into its protective wall. But as he adds building blocks, he also loses them, temporarily leaving gaps in his defenses that allow the antibiotic to sneak in and kill him.

“Antibiotics are a little like a crowbar that helps the bricks come out of the wall,” says Edwards. “The outer membrane doesn't disintegrate, it doesn't fall off. But there are clearly gaps through which the antibiotic can then get to the second membrane.”

He and his colleagues also figured out why the antibiotic doesn't always work: it only affects bacteria which were active and growing. When the bacteria were dormant (a state they can enter to survive environmental stress, such as lack of nutrients), polymyxin B was ineffective because it did not produce its armor.

However, researchers have found that providing sugar coli the cells woke them up from this dormant state, and within 15 minutes armor production resumed and the cells were killed. The same is expected to apply to another polymyxin antibiotic used for therapeutic purposes, polymyxin E.

Edwards says it's possible to target dormant bacteria by giving people sugar, but there's a danger of awakening these pathogens from their dormant state. “It's not necessary for the bacteria at the site of infection to start multiplying quickly, because that has its downsides,” he says. Instead, he adds, different drugs could be combined to bypass the hibernation state without awakening the bacteria.