A potent plant toxin that uniquely kills harmful bacteria has emerged for decades as one of the strongest antibiotic candidates.
Scientists say albicide can kill superbugs like E.coli and salmonella, which are becoming increasingly resistant to modern medicine.
It is produced by a sugarcane pathogen called xanthomonas albilineans, which causes devastating leaf scald disease in plants.
It is thought that albicidin was used by the pathogen to attack sugarcane, which allowed it to spread.
Scientists have known for some time that albicide is very effective at killing superbugs like the notorious E.coli as they become increasingly resistant to antibiotics.
This means researchers are racing to develop effective new drugs.
While experiments have shown albicide to be promising, its pharmaceutical development has so far been hampered because scientists do not know exactly how it interacts with its target, a bacterial enzyme called gyrase, with DNA.
This enzyme binds to DNA and, in a series of graceful movements, twists it in a process called supercoiling, which is vital for cells to function properly.
Now, researchers in the UK, Germany and Poland have taken advantage of advances in a technique called transmission electron microscopy that allows samples to be examined at temperatures as low as minus 273C.
They found that albicidine forms an L shape that allows it to interact with both gyrase and DNA in a unique way.
In this state, gyrase can no longer act to bring the DNA ends together, and albicide acts like a switch between the two gears.
The researchers say the way albicide interacts with gyrase is sufficiently different from existing antibiotics that the molecule and its derivatives could work on most current antibiotic-resistant bacteria.
From the John Innes Center in Norwich, study author Dr. Dmitry Ghilarov said: “It seems that due to the nature of the interaction, albicide targets a really important part of the enzyme and it is difficult for bacteria to develop resistance to it.
“Now that we have a structural understanding, we can look at further exploiting this binding pocket and make further modifications to albicide to improve its efficacy and pharmacological properties.”
The team has already used their observations to make improved versions of the antibiotic.
Tests have found that these new versions are effective against dangerous infections such as E.coli and salmonella.
Dr Ghilarov said: “We believe this is one of the most exciting new antibiotic candidates in years.
“It has extremely high efficacy at small concentrations and is highly effective against pathogenic bacteria, including those resistant to commonly used antibiotics such as fluoroquinolones.
“This molecule has been around for decades. Now, advances in cryo-electron microscopy have made it possible to determine the structures of even the most detailed protein-DNA complexes.
“Being the first to see that the molecule is bound to its target and how it works is a tremendous privilege and the greatest reward a scientist can have.”
– The results are published in the journal Nature Catalysis.