A team of researchers from the University of Illinois have made a breakthrough in understanding how a powerful antibiotic agent is made in nature. By solving the decades-old mystery of how the naturally occurring antibiotic nisin is given its structure by the action of enzymes, the team have opened the way to the discovery, production and study of dozens of similar compounds. This type of compound could be useful in fighting food-borne diseases or dangerous microbial infections, and as an added bonus, the compounds also have properties that make it difficult for pathogens to develop resistance to them.
The team, led by chemistry professor Wilfred van der Donk and biochemistry professor Satish K. Nair, focused on a particular class of compounds, many of which have antibiotic properties. Nisin is the most famous of these, and is a naturally occurring compound in milk that can be produced in the lab and added to foods as a preservative. It has been used effectively to combat food-borne pathogens since the late 1960s “without substantial development of resistance,” notes the paper, which has just been published in the journal Nature.
For years, scientists have wondered how amino acid chains, known as peptides, are manipulated into the forms that give compounds such as nisin their special microbe-fighting properties. “Peptides are a little bit like spaghetti; they’re too flexible to do their jobs,” said Professor van der Donk. “So what nature does is it starts putting knobs in, or starts making the peptide cyclical.” An enzyme called a dehydratase is responsible for forming nisin into a five-ringed structure, which is essential to its antibiotic function.
Dehydratase, as you might expect, dehydrates the peptide to begin forming its shape, but the team then discovered that it used both the addition and removal of the amino acid glutamate to work the peptide into its final ringed form. As the UI statement on the breakthrough reveals, “Two of the rings 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.”
Of the future possibilities as a result of the breakthrough van der Donk says, “In this study, we solve a lot of questions that people have had about how dehydration works on a chemical level. And it turns out that in nature a fairly large number of natural products – many of them with therapeutic potential – are made in a similar fashion. This really is like turning on a light where it was dark before, and now we and other labs can do all kinds of things that we couldn’t do previously.”