Researchers from the University of Illinois uncovered a breakthrough by unlocking how a powerful antibiotic is made in nature. This breakthrough solves a mystery that's gone on for decades, opening up new opportunities for research into similar molecules that are likely to have medical use.
For the study published in the journal Nature, the researchers focused on a compound class that includes dozens of compounds featuring antibiotic properties. The most famous of the compounds is called nisin, a natural milk-derived product that can be added to food as preservative when synthesized in the lab. Since the 1960s, nisin has been utilized for combating pathogens found in food.
The gene sequence for nisin has long been known to researchers, allowing them to assemble amino acid chains called peptides that can be encoded by the gene. However, peptides undergo several changes before achieving their final function and form. These changes have baffled researchers for over 25 years but it is these changes that the study addressed.
Peptides follow a spaghetti-like structure so they are too flexible to function properly on their own. Nature steps in by putting in knobs or turning peptides cyclical with the help of special enzymes. For nisin, the enzyme dehydratase zaps out water, helping give the antibiotic its final form.
By identifying dehydratase, researchers have taken the first step in converting peptides into five-ringed structures. The rings impart antibiotic function to nisin, disrupting the production of cell walls in bacteria while punching through existing bacterial membranes.
Previous studies have already identified dehydratase as the enzyme involved in the changes nisin undergoes but researchers have not been able to determine how exactly dehydratase affected the compound.
Specifically, dehydratase added and eliminated glutamate in nisin. The enzyme was able to achieve two different kinds of action because it interacted with nisin in two separate ways, grasping one part of the peptide to keep it steady while another part of the compound was installing the ring structures.
"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," said research co-lead Wilfred van der Donk, a chemistry professor at the University of Illinois.
Biochemistry professor Satish K. Nair rounds up the research team as co-lead, along with Manuel A. Ortega, Mark C. Walker, Qi Zhang, and Yue Hao.
