Old antibiotic colistin may hold the key to treat superbugs, reveal researchers from Imperial College London, UK (1). Researchers finally unveil how this antibiotic can punch holes and destroy some of the most dangerous and hard to treat bacteria. What’s more, the team also identified a possible way of making this antibiotic even more effective at killing bacteria.
Colistin – also known as polymyxin E – is an antibiotic typically only prescribed to patients as a last resort to treat some of the nastiest multidrug-resistant Gram-negative infections, including pneumonia.
First described in 1947, colistin is one of the very few antibiotics still active against superbugs, including E. coli, Pseudomonas aeruginosa, Klebsiella pneumoniae, or Acinetobacter baumannii. This treatment can be injected into a vein or into a muscle, as well as inhaled in the form of colistimethane sodium, or applied to the skin or taken by mouth in the form of colistin sulfate.
Despite being known and used for over 70 years, researchers have struggled to understand its mechanism of action. Finally, a team from Imperial College London unveiled this mystery and revealed how colistin can actually punch holes in the bacteria, popping them like balloons.
One aspect that unites all superbugs is that they have two skins – called membranes – which makes them very difficult to kill. It turned out colistin can puncture holes through these armoured membranes and destroy the bacteria.
The team discovered that colistin targets a chemical called lipopolysaccharide (LPS) present in the membranes, even though there’s only a tiny amount in the second layer. “It sounds obvious that colistin would damage both membranes in the same way, but it was always assumed colistin damaged the two membranes in different ways”, said Dr Andrew Edwards, from Imperial’s Department of Infectious Disease. “There’s so little LPS in the inner membrane that it just didn’t seem possible, and we were very sceptical at first. However, by changing the amount of LPS in the inner membrane in the laboratory, and also by chemically modifying it, we were able to show that colistin really does puncture both bacterial skins in the same way – and that this kills the superbug”,
After deciphering the mechanism, the team turned their attention to see if they could use this information to boost colistin’s killing abilities. Using Pseudomonas aeruginosa, a bacteria that cause lung infections in people suffering with cystic fibrosis, the researchers combined colistin and a new experimental antibiotic called murepavadin. The result was brilliant: murepavadin increased the amount of LPS in the inner membrane, making it much easier for colistin to punch holes in it and kill the bacteria.
Murepavadin is only experimental at this stage, but clinical trials are due to start soon. If these trials are successful, the colistin / murepavadin duo could represent a powerful treatment to a vast range of superbugs. “As the global crisis of antibiotic resistance continues to accelerate, colistin is becoming more and more important as the very last option to save the lives of patients infected with superbugs. By revealing how this old antibiotic works, we could come up with new ways to make it kill bacteria even more effectively, boosting our arsenal of weapons against the world’s superbugs”, said Akshay Sabnis, lead author of the study.
(1) Sabnis A, Hagart K et al. (2021) Colistin kills bacteria by targeting lipopolysaccharide in the cytoplasmic membrane. eLife 2021;10:e65836 DOI: 7554/eLife.65836