Here’s How Mysterious Last-Resort Antibiotics Kill Bacteria


To kill drug-resistant bacteria, “last resort” antibiotics borrow a tactic from Medusa’s playbook: petrification.

New high-resolution microscope images show that a class of antibiotics called polymyxins crystallize the cell membranes of bacteria. The honeycomb-shaped crystals that form transform the generally supple skin of the fat molecules of the microbes into thin brittle leavesresearchers report on October 21 to Nature Communication. When the petrified membranes break, the bacteria die.

The discovery came as a complete surprise, says Sebastian Hiller, a structural biologist at the University of Basel in Switzerland.

Hiller, biophysicist Selen Manioğlu and their colleagues had used the antibiotics as a control for a different experiment. When the researchers turned on their microscopes, “we saw these waffles,” Hiller says. “I immediately recognized, wow, this must be something special.”

Polymyxin antibiotics like colistin were discovered in the 1940s and are now used as a powerful last resort defense against bacteria that have developed resistance to most other drugs. Researchers already knew that polymyxins somehow interfere with bacterial cell membranes. But no one had imagined a scenario like the “waffles” discovered by the team.

A microscopic photo of bacterial cell membranes in a hexagon "waffle" pattern
Bacterial cell membranes are usually soft and smooth, but polymyxin antibiotics crystallize the membranes into brittle sheets of hexagonal ‘waffles’, seen here in atomic force microscopy imaging.S. Manioglu

In the new study, Hiller and his colleagues exposed pieces of cell membrane from Escherichia coli at different concentrations of colistin. Atomic force microscopy imaging revealed that crystals formed at the minimum concentrations required to kill bacteria. Strains resistant to colistin exposed to the drug did not form crystals.

The results indicate that polymyxins act by organizing the cell membrane into a crystalline structure that makes it brittle and vulnerable. “It’s something that hasn’t even been assumed until now,” says Markus Weingarth, a biochemist at Utrecht University in the Netherlands who was not involved in the work. “This is a very important study. I would even say that it is a breakthrough.

Exactly how polymyxins crystallize cell membranes remains unclear. It’s a problem because some bacteria have developed resistance to polymyxins and become more widespread (SN: 05/27/16; SN: 10/30/90). Without more studies like this to help reveal how drugs work, scientists can’t effectively modify antibiotics to make them more effective, Weingarth says.

Hiller hopes this first glimpse of the petrifying powers of polymyxins will help scientists fight antibiotic resistance.

“Understanding these concepts will certainly bring a lot of ideas – and the potential to make new drugs,” says Hiller.


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