Lying among thousands of bacterial strains in a collection of natural specimens at the Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology, several fragile vials contained something unexpected and possibly very useful.
Writing in the journal Nature Chemical Biology, a team led by chemist Ben Shen, Ph.D., described the discovery of two new enzymes with unique useful properties that could help fight human diseases including cancer. The discovery, published last week, offers potentially easier ways to study and produce complex natural chemicals, including those that could become drugs.
The contribution of bacterial chemicals to the history of drug discovery is remarkable, said Shen, who directs the Institute’s Center for Natural Product Discovery, one of the largest collections of microbial natural products in the world.
“Few people realize that nearly half of the FDA-approved antibiotics and anticancer drugs on the market are or are inspired by natural products,” Shen said. “Nature is the best chemist to make these complex natural products. We are applying modern genomic technologies and computational tools to understand their fascinating chemistry and enzymology, and this is driving progress at an unprecedented rate. These enzymes are the latest exciting example.”
The enzymes the team discovered have a descriptive, if unwieldy, name. They are called “cofactor-free oxygenases”. This means that bacterial enzymes pull oxygen from the air and incorporate it into new compounds, without requiring the typical metals or other cofactors to initiate the necessary chemical reaction.
This new way of synthesizing defense substances would provide a survival advantage, allowing the body to fend off infections or invaders. And because enzymes are to chemists what drills or saw blades are to a carpenter, they offer scientists new ways to create useful things, said the paper’s first authors, postdoctoral researchers Chun Gui, Ph.D., and Edward Kalkreuter, Ph.D. .
Immediately, the discovery of the enzymes, TnmJ and TnmK2, solves a mystery of how a potential antibiotic and anticancer compound first discovered by the Shen lab in 2016, tiancimycin A, achieved such potency, Gui and Kalkreuter said.
The enzymes allow the bacteria to produce compounds to target and break down DNA, Gui said. This would be extremely useful for fighting a virus or other microbe — or for killing cancer.
Tiancimycin A is being developed as part of an antibody therapy that targets cancer. These types of antibody-drug combination therapies represent a rapidly developing new approach to fighting cancer. But a critical step in using tiancimycin A as an antibody payload is enough to be studied on a larger scale. This proved to be a challenge.
“Even after we identified genes responsible for coding for tiancimycin A, many of the steps required for its synthesis could not be predicted,” Gui said. “The two enzymes described in the current study are highly unusual.”
Tiancimycin A was first found in a soil-dwelling bacterium, a type of Streptomyces from the strain collection at the Natural Products Discovery Center. To make its powerful chemical weapon, the agency had to solve a problem. It had to somehow break three very strong carbon-carbon bonds and replace them with more reactive carbon-oxygen bonds. For a long time, scientists could not understand how bacteria accomplished this feat.
Cracking the mystery involved finding other tiancimycin A-like natural product-producing bacteria among the institute’s Natural Products Discovery Center collection of 125,000 bacterial strains, and analyzing their genomes to look for evolutionary clues.
The historic collection has long been housed in the basement of a pharmaceutical company, collected decades after the discovery of penicillin in the scientific community’s hopeful rush to find the next big antibiotic. The collection has produced several historically important drugs over the years, including the anti-tuberculosis antibiotic streptomycin and the organ transplant drug sirolimus. But the majority of the freeze-dried bacterial strains in the collection had rested in their glass vials, unexplored.
In 2018, Shen won a competition for the collection so that it could be fully explored in an academic setting, where it would be open to science. His team is now developing ways to study the strains, read their genomes, and file the information into a searchable database for access by the scientific community. Modern genome sequencing and bioinformatics techniques show that there may be as many as 30 interesting gene clusters in each strain of bacteria they study, and many of them encode natural products that have never been documented by scientists before, said Shen, who is a member of the UF Health Cancer Center.
The discovery of the new cofactor-free enzymes is just the latest example of the chemical wealth found in The Wertheim UF Scripps Institute collection, Shen said. Their discovery has sparked new excitement about further investigating why the unique chemistry evolved and how it might prove useful.
“This publication highlights how many surprises nature still has for us,” said Shen, “It can teach us a lot about fundamental chemistry and biology, and give us the tools and inspiration we need to translate laboratory findings into drugs that affect society and address many problems facing humanity.”