Biochemists Uncover Nature's Own Process of Antibiotic Production

Nature has been making antibiotics a whole lot longer than human scientists. A potent example is nisin, a naturally-occurring, broad-spectrum antibiotic currently used by humans as a food preservative. A member of the lantibiotic class of antibiotics, nisin is naturally produced by some varieties of bacteria to fight against other bacteria.

Nisin is a peculiar thing, however, and has so far eluded complete chemical synthesis. Instead, it's produced by culturing the bacteria lactococcus lactis on substrates of milk or dextrose. Nisin is used by humans most commonly in the production of processed foods, where, as an additive, it can extend shelf lives by fighting against pathogenic (bad) bacteria and delaying spoilage.

A paper out in today's edition of Nature describes for the first time exactly how nisin is created and shaped in nature, solving a decades-old mystery and potentially opening the door to better and more resistance-resistant antibiotic compounds.

Nisin's unique structure and mechanism of action would seem to hold a lot of promise for the development of new and better antimicrobal drugs. While scientists have been able to replicate the amino acid sequence underlying nisin, the next step, how those sequences take shape, has been elusive until now.

Nisin is a peptide, a string of 50 or fewer amino acids. Peptides, together as polypeptides, are often the building blocks of the much larger and more organized arrangements of amino acids that make up proteins. Recreating them is difficult in part because it's not just a matter of just putting a bunch of chemical puzzle pieces together—nisin isn't born ready to slay bacteria, it's also the product of an environment.

The end nisin product is a five-ring structure that's crucial for its antibiotic abilities. Two of the rings work to disrupt the target's ability to make cell walls, while the other three punch holes in the bacterium's protective membrane. The mystery has been in how exactly the nisin peptide takes this five-ring shape.

"The lantibiotic nisin has been used worldwide in the food industry for more than 40 years without substantial development of resistance," the paper notes. "This unique property is thought to be a consequence of nisin's dual mode of action."

It's been revealed previously that the enzyme dehydratase is the key, but its precise role has gone undescribed until now. Part of the mystery is in the fact that dehydratase appears to serve two unique functions, making it something of an anomaly for such a simple structure. Generally, it removes water from the nisin compound, as the name implies, and this dehydration helps give the peptide its three-dimensional shape.

As the current report explains, dehydratase does its work via the amino acid glutamate (the same stuff you'd find in MSG or soy sauce). Using x-ray crystallography, the researchers were able to spy on the dehydratase as it bound itself to the nisin peptide and went to work, both adding and removing glutamate to the peptide's structure.

Curiously, the dehydratase is able to grasp one portion of the peptide to hold it steady while it helps install the nisin's key ring structures, just like a tiny robot assembly line. "There's a part of the nisin precursor peptide that is held steady, and there's a part that is flexible. And the flexible part is actually where the chemistry is carried out," said biochemist Satish K. Nair, the study's lead author, in a statement.

"In this study, we solve a lot of questions that people have had about how dehydration works on a chemical level," added co-author Wilfred van der Donk. "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."