In a breakthrough, researchers, including one of Indian-origin, have solved a decades-old mystery into how a broad class of natural antibiotics are made.
The discovery opens up new avenues of research into thousands of similar molecules, many of which are likely to be medically useful, researchers said.
The team focused on a class of compounds that includes dozens with antibiotic properties. The most famous of these is nisin, a natural product in milk that can be synthesised in the lab and is added to foods as a preservative.
Nisin has been used to combat food-borne pathogens since the late 1960s.
Researchers have long known the sequence of the nisin gene, and they can assemble the chain of amino acids (called a peptide) that are encoded by this gene.
But the peptide undergoes several modifications in the cell after it is made, changes that give it its final form and function. Researchers have tried for more than 25 years to understand how these changes occur.
For nisin, an enzyme called a dehydratase removes water to help give the antibiotic its final, three-dimensional shape.
This is the first step in converting the spaghetti-like peptide into a five-ringed structure, said University of Illinois chemistry professor Wilfred van der Donk, who led the research with biochemistry professor Satish K Nair.
The rings are essential to nisin's antibiotic function: Two of them disrupt the construction of bacterial cell walls, while the other three punch holes in bacterial membranes.
This dual action is especially effective, making it much more difficult for microbes to evolve resistance to the antibiotic, researchers said.
Previous studies showed that the dehydratase was involved in making these modifications, but researchers have been unable to determine how it did so.
This lack of insight has prevented the discovery, production and study of dozens of similar compounds that also could be useful in fighting food-borne diseases or dangerous microbial infections, van der Donk said.
Through a painstaking process of elimination, Manuel Ortega, a graduate student in van der Donk's lab, established that the amino acid glutamate was essential to nisin's transformation.
"They discovered that the dehydratase did two things. One is that it added glutamate (to the nisin peptide), and the second thing it did was it eliminated glutamate," said Nair.
The research was published in the journal Nature.
