The cyanobacteria species that produces gatorbulin-1, tentatively identified as Lyngbya confervoides, forms these reddish-green, hair-like structures which are a collection of connected single cells rather than a true multicellular organism.
Photo: Raphael Ritson-Williams
I've written several articles recently showing why biodiversity is important because, if for no other reason, it represents a potential untapped resource of useful chemicals such as antibiotics, fungicides, etc.
Now here's another one, this time yielding a potential anti-cancer drug.
It was found by a team of scientists from the Smithsonian’s National Museum of Natural History and University of Florida in blue-green algae, or cyanobacteria, tentatively identified as Lyngbya confervoides, in the sea off south Florida. These cyanobacteria are simple organisms that form hair-like filaments which look superficially like plants but which are just simple chains of single cells with no specialisation or division of labour.
The ocean is relatively unexplored. It is where most of our biological and chemical diversity is undiscovered. We’re interested in locations with high marine biodiversity, because that means there are many organisms communicating and fighting, using bioactive compounds that we can pivot for drug development...
It’s really chemical warfare out in the oceans. The more warfare or communication that is out there, the better for us because it means more active compounds that we can try to put to good use for humankind.
Unlike more complex organisms, which have claws, teeth or fierce noises for defence, bacteria use chemicals. They also use chemicals as signals. In effect, the seas are places of chemical warfare between competing species and predator-prey relationships and these organisms have been at it for hundreds of millions of years in arms races which continually refine these chemicals and fit them for purpose. For example, L. confervoides has an uneasy relationship with corals, which it can over-grow, so corals fight back and L. confervoides needs to counter that attack, so we have a classic arms race.It’s really chemical warfare out in the oceans. The more warfare or communication that is out there, the better for us because it means more active compounds that we can try to put to good use for humankind.
Dr. Hendrik Luesch, lead author
Director of the Center for Natural Products, Drug Discovery and Development
University of Florida, USA
Director of the Center for Natural Products, Drug Discovery and Development
University of Florida, USA
We have studied a series of compounds called quorum sensing inhibitors that effect the chemical cues that bacteria use to communicate...
Nature has already optimized these compounds and, in some cases, we don’t know what for. My strong feeling as a chemical ecologist is that they are being made for a purpose. Gatorbulin-1 wasn’t made to be a potential anti-cancer drug or target humans but it’s toxicity to cells is serving some purpose in the cyanobacterium naturally...
We have entire groups of organisms in the ocean that don’t exist on land and have undergone completely different evolutionary pressures over time.
One of these chemicals, known as gatorbulin-1 (GB1), is a cytotoxin and as such has the potential to be used as an anti-cancer drug, hitting malignant cells harder than normal cells. It's actual use by L. confervoides is unknown but is presumed to be part of its defensive armoury.Nature has already optimized these compounds and, in some cases, we don’t know what for. My strong feeling as a chemical ecologist is that they are being made for a purpose. Gatorbulin-1 wasn’t made to be a potential anti-cancer drug or target humans but it’s toxicity to cells is serving some purpose in the cyanobacterium naturally...
We have entire groups of organisms in the ocean that don’t exist on land and have undergone completely different evolutionary pressures over time.
Dr. Valerie Paul, Co-author
Chemical ecologist and head scientist at the Smithsonian Marine Station.
Chemical ecologist and head scientist at the Smithsonian Marine Station.
The Smithsonian's News item explains how the team identified the potential of this chemical:
But finding a new compound, like GB1, and learning enough about it to confidently say that it has the potential to be a new drug can be a lengthy process — which doesn’t include the additional time and testing it then takes to turn the compound into a safe, approved and functional drug.The teams findings were published a couple of days ago:
The first part of the process is compound isolation and demonstrating that the purified compound can selectively kill cancer cells. Prompted by this finding, Luesch’s team worked to figure out how to synthesize the compound in the lab. Having a reliable way to produce GB1 is important in being able to conduct in-depth studies.
“We usually can’t go out and constantly collect more of the cyanobacteria,” Luesch said. “It’s fun diving and snorkeling but, at the end of the day, you’re lucky if you find enough of the organism again to isolate enough material for advanced studies. As organic chemists, we can recreate these natural molecules in larger quantities in the laboratory without relying on the cyanobacteria.”
GB1’s novelty added additional steps to the synthesis process. “There are so many ways to put a molecule together and you don’t necessarily know upfront what is the best way,” Luesch said.
Next, Luesch’s team tested the compound against numerous distinct cancer cells to figure out how GB1 worked. The team found that GB1 targets a protein in cells called tubulin, which is the protein that cells require during cell division and use to build their inner scaffolding. While there are already chemotherapy drugs that target tubulin, Luesch and collaborators in Spain showed that GB1 is special because it interacts with tubulin in a new way.
Corals and cyanobacteria can have a strained relationship as the bacteria can become overgrown on corals and cause them harm. L. confervoides has overgrown a gorgonian coral.
Photo: Raphael Ritson-Williams
With a mass extinction in progress due to human activity, in what scientists have called the Anthropocene because of our impact on the planet and it's future geological record, we are in danger of losing an untold number of potentially useful chemicals. For this reason alone, we need to maintain the planet's biodiversity, and especially that of the oceans, because this is still a major untapped source of chemicals such as this one.Significance
Natural products provide the inspiration for most drugs, and marine natural products, in particular, are emerging as promising new therapeutics with new targets or mechanisms of action. Pharmacological targeting of tubulin dynamics has been a validated strategy for cancer therapy for decades, yielding structurally diverse natural products and derivatives, including paclitaxel, vincristine, maytansine, and eribulin, targeting six known and different binding sites. We discovered a chemical scaffold from marine cyanobacteria that targets a seventh tubulin binding site. We report the entire spectrum of the discovered chemical and biological novelties, including the isolation, structure determination, and chemical synthesis of the natural product, and the investigation of its mechanism of action, target identification, and binding mode elucidation at the atomic level.
Abstract
Tubulin-targeted chemotherapy has proven to be a successful and wide spectrum strategy against solid and liquid malignancies. Therefore, new ways to modulate this essential protein could lead to new antitumoral pharmacological approaches. Currently known tubulin agents bind to six distinct sites at α/β-tubulin either promoting microtubule stabilization or depolymerization. We have discovered a seventh binding site at the tubulin intradimer interface where a novel microtubule-destabilizing cyclodepsipeptide, termed gatorbulin-1 (GB1), binds. GB1 has a unique chemotype produced by a marine cyanobacterium. We have elucidated this dual, chemical and mechanistic, novelty through multidimensional characterization, starting with bioactivity-guided natural product isolation and multinuclei NMR-based structure determination, revealing the modified pentapeptide with a functionally critical hydroxamate group; and validation by total synthesis. We have investigated the pharmacology using isogenic cancer cell screening, cellular profiling, and complementary phenotypic assays, and unveiled the underlying molecular mechanism by in vitro biochemical studies and high-resolution structural determination of the α/β-tubulin−GB1 complex.
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