Understanding how antibiotic scaffolds are constructed in nature can help scientists prospect for new classes of antibiotics through DNA sequencing and genome mining. Researchers have used this knowledge to help solve the X-ray crystal structure of the enzyme that makes obafluorin — a broad spectrum antibiotic agent made by a fluorescent strain of soil bacteria. The new work from Washington University in St. Louis and the University at Buffalo was published July 31 in the journal Nature Communications.
A multi-part enzyme called a nonribosomal peptide synthetase produces the highly reactive beta-lactone ring that is responsible for obafluorin’s antimicrobial activity.
“Obafluorin has a novel structure compared to all FDA-approved antibiotics,” said Timothy Wencewicz, assistant professor of chemistry in Arts & Sciences. “In the long term, we really need new structural classes of antibiotics that have never been contaminated by clinical resistance from established antibiotic classes.”
These chemicals could be used as next-generation antibiotics for humans, or even to benefit the agriculture sector, Wencewicz noted — as researchers strive to engineer seed treatments and biopesticides to support plant systems capable of making enough food to feed the 9.6 billion people projected to live on this planet by 2050.
The new work provides a useful road map that shows how individual protein domains in the ObiF1 enzyme are stitched together in three-dimensional space. An enzyme’s structure is fundamental to almost every function it performs.
“The solution of this structure expands on previous discoveries to provide views of the molecular interactions between catalytic domains in a brand new way,” said Andrew M. Gulick, associate professor in the department of structural biology in the Jacobs School of Medicine and Biomedical Sciences at the University at Buffalo. “This is a brand new class of compounds, and we’ve never had the molecular vision to appreciate how they are produced.”
Pinning down a new antibiotic from nature
Obafluorin is made by a fluorescent strain of soil bacteria that forms biofilms on plant roots. Obafluorin was originally discovered in 1984, but it wasn’t until 2017 that Wencewicz uncovered the genetic blueprint of the enzyme that makes the molecule’s bio-active components. That discovery marked the first time that anyone had been able to pin down a beta-lactone forming enzyme from nature, and recreate it in the laboratory.
Like penicillin, obafluorin has a four-membered ring — sometimes called an enchanted ring. A four-membered ring puts strain on bond angles that carbon prefers to adopt. But because a four-member ring is unstable, these molecules are also short-lived and difficult to make.[…]