Researchers from UC San Diego’s Scripps Institution of Oceanography andSkaggs School of Pharmacy and Pharmaceutical Sciences have developed a new approach to scour the oceans for novel compounds that could become the medicines and products of tomorrow.
The method, described in a paper published June 19 inNature Communications, captures chemical compounds directly from the sea and could allow researchers to more fully tap the biochemical potential of the world’s oceans for the benefit of humanity.
Already the new technique has facilitated the discovery of several new compounds, one of which shows promising activity against cancer cells and potentially useful effects on heart muscle function.
"What's particularly exciting is that we found these novel compounds from a single deployment site," said Scripps Oceanography microbiologistPaul Jensen, a co-author of the study, which was funded by the National Institutes of Health. "This hints at the vast chemical diversity waiting to be discovered in our oceans."
This innovation comes at a crucial time when antibiotic resistant bacteria are on the rise and thediscovery of new antibiotics and other medicines has slowed. By providing access to previously unexplored chemical space, the new method could expand and accelerate drug discovery efforts and lead to new treatments for various diseases. Beyond medicines and products, the approach could also be used to better understand the complex chemistry of the marine environment, including ecological interactions mediated by these compounds.
“The ocean remains a vastly untapped source for potential new medications,” saidTadeusz Molinski, co-corresponding author of the study and a chemist jointly appointed with the Skaggs School of Pharmacy and Pharmaceutical Sciences and the Department of Chemistry and Biochemistry at UC San Diego. “This new method substantially enhances our ability to identify marine-based compounds that could become life-saving therapies.”
The study describes the technique, known as small molecule in situ resin capture (SMIRC), and tests its potential for natural product discovery. The approach involves placing mesh pouches filled with small porous resin-based beads in the ocean and then retrieving the beads to see what they’ve captured. Any compounds stuck to the beads can then be tested for desirable properties. If a given compound shows promise, the researchers begin discerning its chemical structure, figuring out which microbes produce it and then culturing those microbes in the lab to harvest those and any other compounds the organisms produce.
The innovation of SMIRC is that it inverts the traditional approach to what researchers call microbial natural product discovery. The traditional method involves culturing microbes first and then trying to determine if they produce potentially therapeutic compounds in the lab—which requires significant time and effort with uncertain rewards.
This technique begins with the compounds themselves. This allows researchers to efficiently screen large numbers of compounds for useful properties before expending the effort involved in identifying which microbes produce those compounds and how those organisms can be cultured in the lab. Additionally, modern genetic analyses suggest that many microbes already well known to science have the genetic potential to produce compounds that scientists have been unable to coax them into creating in the lab. Capturing compounds directly from the organisms’ natural habitats could help avoid this bottleneck, one that has limited product discovery to what microbes can be made to produce in the lab.
“When we culture an organism in the lab, they don’t necessarily want to make what we want them to make without the right stimuli,” said Jensen. “This creates difficulties and limits the compounds we discover. Instead, we wanted to go to the ocean where these microbes live and see what they produce in a natural setting.”
Jensen said he and his co-authors were inspired to develop SMIRC after encountering similar porous resins being used in the ocean to monitor for compounds produced during harmful algal blooms such as the neurotoxin domoic acid.
“We wondered if we could use similar resins to capture the broadest possible range of marine compounds,” said Jensen. “The answer was yes. From just one deployment, we came back with an embarrassment of riches in terms of the number of what appear to be new molecules.”
To test the method, researchers deployed 12-inch discs with the resin beads sandwiched between fine mesh in various marine environments near San Diego, including seagrass meadows and rocky reefs.
Next, they identified the compounds captured by the resin and tested those compounds for potential antibiotic activity as an initial screening. For the compounds that showed antibiotic potential, the team checked public databases to see if the chemicals were known to science. The researchers purified and isolated any new compounds so they could determine the compounds’ chemical structures.
Then the team conducted a broader array of biological tests with collaborators at UC San Diego and UC San Francisco, including how the new compounds impacted cancer cells, their effects on the beating of heart cells grown from stem cells and whether the compounds inhibited various enzymes involved in viral infections. Finally, the researchers conducted genetic analysis on DNA retrieved from the sites where the compounds were collected as a first step towards identifying their microscopic authors.
In collaboration with Molinski, the researchers identified a new compound that they dubbed cabrillostatin in honor of Cabrillo State Marine Reserve where it was collected. The new substance showed promising biological activities, including effects on cancer cells and heart muscle function. Ten other compounds isolated from the initial deployments of the resins also appeared to be new to science.
“This study shows that it is actually possible to isolate and fully characterize previously unknown natural products directly from the environment where they are produced,” saidAlexander Bogdanov, a Scripps researcher and the study’s first author.
As the team continues to refine this technique, they hope to deploy SMIRC in more places around the world. Later this summer, the researchers plan to collect compounds from the intertidal zone at Point Loma or the kelp forests near La Jolla.
The research builds upon the marine natural products research led by theCenter for Marine Biotechnology and Biomedicine at Scripps. Jensen is also part of the team that discovered a deep-sea microbe with anti-cancer properties. That compound, known as salinosporamide A, went throughclinical trials as a potential treatment for the brain cancer glioblastoma.
In addition to Bogdanov, Jensen and Molinski, Mitchell Muskat of Scripps and Alexander Chase of Scripps and Southern Methodist University were co-authors on the study. Mariam Salib, Stephanie Luedtke, Elany Barbosa da Silva and Anthony O’Donoghue of UC San Diego as well as Lani Wu, Steven Altschuler and Heinz Hammerlindl of UC San Francisco also co-authored the study.
