Home » After 70 Years Mystery Of Deadly ‘Last Resort’ Antibiotic Solved

After 70 Years Mystery Of Deadly ‘Last Resort’ Antibiotic Solved

P. aeruginosa being ‘popped’ by colistin  antibiotic
P. aeruginosa being ‘popped’ by colistin
Source : Imperial College London

In the eternal race between bacteria and antibiotics, deadly superbugs with resistance to humanity’s most significant life-saving medicines continue to emerge and evolve.

It’s a growing crisis, but thankfully we aren’t entirely powerless against the scourge of antibiotic resistance.

In medical scenarios where frontline-treatments fail to help patients, doctors can turn to so-called drugs of last resort – treatments put aside until the last minute has come, after prioritized therapies have not worked out .

Drugs of last resort could also be held back for variety of reasons, including side effects, cost factors, patient considerations, and more.

In the antibiotics context, there’s a further pretext: We don’t want highly resistant bacteria to find out the way to resist these drugs too, so clinicians limit their use wherever possible.

Colistin is one such medicine. one among only 17 ‘Reserve Group’ antibiotics on the World Health Organization’s List of Essential Medicines, colistin was first discovered in 1940s, and used as a last resort against multi-drug-resistant pathogens like Escherichia coli , Klebsiella pneumoniae, and Pseudomonas aeruginosa.

Colistin isn’t perfect, however. The drug’s toxicity can produce variety of serious side effects, putting a constraint on dosage levels – and at low doses it’s not always effective in patients.

Because of this, there’s a pressing got to know more about how colistin functions. Not only to ascertain if there are ways we will boost its efficacy, but also maybe to save lots of the drug itself: the primary signs of bacterial resistance to colistin began to emerge a decade ago, and have now spread round the world.

“As the worldwide crisis of antibiotic resistance continues to accelerate, colistin is becoming more and more important as very last way to save the lives of patients infected with superbugs,” says microbiologist Akshay Sabnis from Imperial College London within the UK.

“By revealing how this old antibiotic works, we could come up with new ways to form it kill bacteria even more effectively, boosting our arsenal of weapons against the world’s superbugs.”

Strangely enough, for a drug that’s been around for over 70 years, the mechanisms by which colistin ultimately kills bacteria have remained somewhat mysterious. Until now.

In a new study led by Sabnis, researchers conducted experiments with multiple strains of bacteria to research how colistin functions at the molecular level.

Colistin is an example of a polymyxin antibiotic, which works by binding to the outer cellular membrane of gram-negative bacteria, ultimately disrupting the outer membrane then the inner membrane (aka the cytoplasmic membrane).

In so doing, this kills the microbes – punching holes in their bodies to effectively make them pop like balloons.

In this process, colistin targets molecules called lipopolysaccharides within the bacterial outer membrane, but exactly how the antibiotic disrupted the inner barrier was less certain, since the inner membrane contains much lower levels of lipopolysaccharides.

Thanks to new tests with E. coli strains, the researchers confirmed that lipopolysaccharide disruption is additionally what’s liable for destroying the inner cell membrane , even though molecule’s presence there’s much lower.

“It sounds obvious that colistin would damage both membranes within the same way, but it had been always assumed colistin damaged the 2 membranes in several ways,” says molecular microbiologist Andy Edwards, the senior author of the study.

“By changing the quantity of lipopolysaccharides within the inner membrane in laboratory, and also by chemically modifying it, we were ready to show that colistin really does puncture both bacterial skins in same way – that this kills the superbug.”

Even more promisingly, the researchers discovered how to augment colistin’s ability to disrupt the inner membrane, because of an experimental antibiotic called murepavadin, which boosts the amount of lipopolysaccharides in bacterial inner membranes.

Hypothetically speaking, pairing colistin with murepavadin could give former more molecular bullseyes on the balloon to target , and subsequent experiments appeared to bear this line of reasoning out.

In experiments with mice infected by P. aeruginosa bacteria, treatment with either colistin or murepavadin by itself had little or no immediate effect on bacterial load in animals, but the mixture therapy produced a roughly 500-fold reduction in bacterial colony-forming units in only three hours.

While murepavadin is an experimental drug not yet cleared for clinical use in human patients, the new findings indicate a potent path forward – where an old antibiotic and a replacement ally join forces against common enemy.

“It is anticipated that a mixture of colistin and murepavadin could enhance the low treatment efficacy of polymyxin antibiotics and could also limit the toxic side effects related to both compounds by enabling the utilization of lower doses of the drugs,” the authors write in their study.

“Modulation of lipopolysaccharide levels within the cytoplasmic membrane can enhance colistin activity, providing the foundations for new approaches to enhance the efficacy of this antibiotic of last resort .”

The findings were reported In eLife

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