Scientists have discovered how a “last resort”
; antibiotic kills bacteria.
The findings, from Imperial College London and the University of Texas, may also reveal a potential way to make the antibiotic more powerful.
The antibiotic colistin has become the last resort to treat infections caused by some of the world’s nastiest superbugs. However, although it was discovered more than 70 years ago, the process by which this antibiotic kills bacteria has so far been a mystery.
Now researchers have discovered that colistin drills holes in bacteria, causing them to pop out like balloons. The work, funded by the Medical Research Council and the Wellcome Trust, and published in the journal eLife, also identifies a way to increase the effectiveness of the antibiotic in killing bacteria.
Colistin was first described in 1947 and is one of the few antibiotics that is active against many of the deadliest superbugs, including E. coli, which causes potentially deadly blood infections, and Pseudomonas aeruginosa and Acinetobacter baumannii, which are often infect the lungs of people receiving mechanical ventilation in intensive care units.
These superbugs have two “skins” called membranes. Colistin pierces both membranes, killing bacteria. However, while colistin was known to damage the outer membrane by targeting a chemical called lipopolysaccharide (LPS), it is not clear how the inner membrane is perforated.
Now a team led by Dr. Andrew Edwards of Imperial’s Department of Infectious Diseases has shown that colistin is also targeted to LPS in the inner membrane, although there is very little of it.
Dr Edwards said: “It sounds obvious that colistin would damage both membranes in the same way, but colistin has always been thought to damage both membranes in different ways. There is so little LPS in the inner membrane that it just didn’t seem possible and we were very skeptical at first. By changing the amount of LPS in the inner membrane of the lab, as well as by chemical modification, we were able to show that colistin really penetrates both bacterial skins in the same way – and that it kills the superbug. ”
The team then decided to see if they could use this new information to find ways to make colistin more effective at killing bacteria.
They focused on a bacterium called Pseudomonas aeruginosa, which also causes serious lung infections in people with cystic fibrosis. They found that a new experimental antibiotic, called murepavadin, caused LPS to build up in the bacterium’s inner skin, making it much easier for colistin to break through and kill the bacteria.
The team says that because murepavadin is an experimental antibiotic, it cannot yet be used routinely in patients, but clinical trials should begin soon. If these trials are successful, it may be possible to combine murepavadin with colistin to provide a powerful treatment for a wide range of bacterial infections.
Akshay Sabnis, lead author of the Department of Infectious Diseases, said: “As the global crisis of antibiotic resistance continues to accelerate, colistin is becoming increasingly important as a last resort to save the lives of patients infected with superbugs. By discovering how this old antibiotic works, we could come up with new ways to make it kill bacteria even more effectively by increasing our arsenal of weapons against the world’s superbugs. “
Reference: Colistin kills bacteria by directing lipopolysaccharide to the cytoplasmic membrane “by Akshay Sabnis, Katheryn LH Hagart, Anna Klöckner, Michele Becce, Lindsay E Evans, R Christopher D Furniss, Despoina AI Mavridou, Molly Mulve Murphy M Steve Davis, Gerald J. Larwie-Momus, Thomas B. Clark and Andrew M. Edwards, April 6, 2021, eLife.
DOI: 10.7554 / eLife.65836